The role of HMGA1 in genome stability: Implications in human cancer.

Introduction
Maintaining the stability of genomic DNA is not only crucial for normal cells but also for the growth, survival and development of tumor cells.To maintain cell viability and genomic stability, there exist complex and precise DNA damage response (DDR) systems in cells, such as non-homologous end junctions (NHEJ), homologous recombination (HR), mismatch repair (also known as MMR), nucleotide excision (NER), etc [1–3]. These systems are related to identifying DNA damage, blocking the cell division cycle, providing accurate DNA repair and promoting abnormal cell apoptosis.
Recent studies have shown that DNA damage persists in cells under various exogenous stresses (such as ultraviolet exposure, ionizing radiation and chemical exposure) and endogenous factors (such as replication errors, cellular metabolism and oxidative stress) [4–7], eventually leading to single-stranded or double-stranded DNA breaks and ultimately cell death. Based on this feature, many DNA-damaging drugs have begun to join the ranks of anti-tumor drugs, promoting tumor cell death by causing DNA damage to tumor cells and achieving anti-tumor therapeutic effects. For example, olaparib, cisplatin (DDP), radiotherapy, etc. Studies have shown that inhibiting FASN can lead to an increase in the content of ceramides and sphingomyelin within cells, causing DNA damage through the formation of DNA double-strand breaks and cell death [8]. When FASN inhibitors are used in combination with olaparib, olaparib induces cell death by blocking DNA damage repair. Chemical resistance is the main obstacle in the treatment of human cancers. The increase in DNA repair capacity is one of the important mechanisms of chemotherapy resistance. YTHDF1 promotes the growth of breast cancer cells both in vitro and in vivo. YTHDF1 promotes the entry of the S phase, DNA replication and DNA damage repair. Overexpression of YTHDF1 makes cells resistant to chemotherapy, while inhibition of YTHDF1 makes breast cancer cells sensitive to doxorubicin, cisplatin and the PARP inhibitor olaparib [9].
In cancer, HMGA1 is overexpressed in nearly all tumor types, with its expression levels correlating with tumor malignancy and poor patient prognosis. This has led to HMGA1 being increasingly proposed as a novel prognostic marker of cancer [10, 11]. High expression of HMGA1 usually leads to chemotherapy resistance in tumor cells. It has been reported that, in esophageal squamous cell carcinoma (ESCC), HMGA1 acts as a key contributor for DDP resistance by inhibiting ferroptosis. Suppression of HMGA1 has been shown to enhance the sensitivity of ESCC cells to ferroptosis. Mechanistically, HMGA1 upregulates the expression of solute carrier family 7 member 11 (SLC7A11), a critical transporter for maintaining intracellular glutathione homeostasis, preventing malondialdehyde (MDA) accumulation, and thereby inhibiting ferroptosis.
Cells with high HMGA1 expression exhibit resistance to DNA-damaging agents such as DDP, olaparib, and topoisomerase inhibitors, facilitating tumor progression and leading to reduced survival rates in mice. We recently observed that HMGA1 increases the resistance of ESCC cells to cisplatin. In tumor models using allograft and genetically engineered mice with HMGA1 overexpression, ESCC development was markedly induced. In contrast, HMGA1 depletion reduced the tumorigenesis of ESCC in mice and restored ESCC sensitivity to DDP by promoting ferroptosis, enhancing therapeutic outcomes [12]. Further investigations into HMGA1’s role in DNA damage revealed that it promotes DNA repair following etoposide-induced damage. HMGA1 is involved in both HR and non-homologous end joining (NHEJ), highlighting its dual functions in maintaining genome stability and contributing to therapy resistance in cancer cells. HMGA1 binds to the DNA damage repair protein PARP1 via its second A-T hook domain and undergoes poly(ADP-ribosyl)ation at residues E47 and E50. This post-translational modification enhances HMGA1’s function in DNA repair. Mechanistic studies have shown that poly(ADP-ribosyl)ation(PARylation) of HMGA1 facilitates the recruitment of Ku70 and Ku80 to sites of DNA damage and promotes the activation of DNA-PKcs, a key player in the DNA repair process. Overexpression of HMGA1 impairs the efficacy of olaparib, a PARP inhibitor, in treating esophageal carcinoma cells and orthotopic esophageal carcinoma. In contrast, inhibition of HMGA1 markedly increases the sensitivity of esophageal cancer cells to olaparib, offering a novel theoretical basis and direction for improving the efficacy of DNA damage-based cancer therapies [12].
In this review, we discuss the structure and function of HMGA1, with a focus on recent discoveries regarding its roles in genomic stability and cell death. Furthermore, we summarize various strategies to inhibit HMGA1 for cancer therapy—including compounds and genetic approaches targeting its structure and function—to provide insights for developing clinical methods to treat HMGA1-driven diseases.

Structure and function of HMGA1
HMGA1 is also referred to as HMGI/Y previously [13]. Human HMGA1a and HMGA1b are encoded by the short arm of chromosome 6. The peptide chain is approximately 100 amino acids in length (10.7–11.7 kDa), classifying it as a low molecular weight histone. Structurally, it contains three conserved, independent AT-hook domains (DNA-binding domains, DBD) and an acidic carboxyl tail. The three AT-hook DNA-binding motifs of HMGA proteins contain the core peptide sequence Pro-Arg-Gly-Arg-Pro (P-R-G-R-P), which enables preferential binding to the minor grooves of A/T-rich B-type DNA sequences [14]. While all three motifs function synergistically during target recognition, the first two AT hooks contribute most significantly to the DNA-binding affinity of HMGA1 [15]. The HMGA1 protein functions as an antagonist to linker histone H1, which binds to the same DNA sequences and maintains chromatin in a tightly packed, transcriptionally inactive state [13]. By contrast, HMGA1 binding introduces substantial structural changes in DNA, resulting in a more open chromatin configuration that facilitates gene transcription.
The charge difference between the AT-hook domain and the acidic carboxyl terminal influences the conformation of DNA upon binding, resulting in structural changes such as DNA bending, straightening, unwinding, looping, or altering DNA topologies [13, 16]. These conformational changes enable the recruitment of transcription factors to specific regulatory regions through enhancers or by competing with histones or chaperones, ultimately affecting gene transcription.The AT-type hook DNA binding motif defines the HMGA family, which consists of HMGA1 and HMGA2. Here, we focus on the HMGA1 subfamily composed of HMGA1a and HMGA1b protein subtypes. These subtypes are produced by selectively spliced mRNA, and the difference lies in the 11 internal amino acids that only exist in HMGA1a. HMGA1b lacks nine amino acids located between the first and second AT-hook motifs compared to HMGA1a, while the rest of their sequences are nearly identical [17, 18].
Beyond its global role as a major regulator of chromatin structure, HMGA1 physically interacts with various transcription factors, such as Sp1,nuclear factor kappa-B (NF-κB), SREBP1, ATF-4, and ETS Proto-Oncogene 1 (ETS1) [12, 19, 20]. These interactions enable HMGA1 to coordinate the assembly of transcriptional complexes at gene promoter and enhancer regions, thereby playing critical roles in specific transcriptional regulation.
HMGA1 is stimulated by multiple Factors, including Inflammation(LPS, DSS), Hypoxia, Viral Infection, and Growth Factors. Oncogenic Transcription Factors(cMYC, AP1), Epigenetic Modifications, DNA Damage(Etoposide), etc. Under these stimulating factors, HMGA1 performs different functions. For example HMGA1 Nrg1/ErbB2, PI3K/CCND1 pathways regulating cell proliferation [21–23], through ATF4/SLC7A11, P27/CDK2/mTOR, p53, miR − 221/TP53INP1/p - ERK, mTOR/ULK1 regulating cell death, DNA repair is involved through proteins such as PARP1,53BP1, and DNA-PK [24, 25]. Of course, it has many other functions. We will summarize and introduce them in the table below (Table 1).

Post-translational modifications of HMGA1 in genome stability
High mobility group (HMG) proteins are non-histone chromosomal proteins involved in chromatin assembly and transcriptional regulation. Due to its essential cellular functions, HMGA1 is highly regulated. It is one of the most heavily post-translationally modified proteins in the nucleus, undergoing various modifications, including phosphorylation, acetylation, ubiquitination, SUMOylation, methylation, and PARylationn. These post-translational modifications affect multiple functions of HMGA1, among which phosphorylation and PARylation have been proven to play a role in regulating DNA stability.

Phosphorylation of HMGA1
HMGA1 is a structural protein that regulates transcription by altering the conformation of DNA upon binding. Post-translational modifications of the HMGA1 protein influences its binding affinity to DNA and regulates its function.
In eukaryotes, chromatin accessibility regulates gene transcription, DNA replication, and DNA repair. Chromatin is not an inert structure; rather, it acts as a guiding DNA scaffold that responds to external signals to regulate functions of DNA [53, 54]. The nucleus is the most rigid organelle, and it undergoes considerable deformation to shrink and pass through the environment. Nuclear rigidity is primarily determined by the nuclear layer and chromatin, which can be influenced by nuclear structural proteins [55–57]. HMGA1 expression levels are correlated with nuclear stiffness, histone H1 phosphorylation status, and changes in chromatin distribution and histone H1 expression [48]. HMGA1 may strongly influence the aggressiveness of cancer cells by promoting chromatin relaxation via a histone H1-mediated mechanism [48]. The HMGA1 protein acts as an antagonist to adaptor histone H1, whereas adaptor histone H4 binds to the same DNA sequence and maintains chromatin in a tightly packed, transcriptionally inactive state. As a result, expression of HMGA1 leads to marked changes in DNA structure, resulting in a more open chromatin state that promotes gene transcription.The kinetic properties of HMGA1a are controlled by the number of functional AT hooks and are regulated by specific phosphorylation patterns. Higher residence times in heterochromatin and chromosomes of HMGA1 are associated with increased levels of HMGA1a phosphorylation compared to euchromatin regions [15].
Numerous studies have shown that phosphorylation of HMGA1 is closely related to its DNA-binding ability. Phosphorylation can induce a conformational change of HMGA1a from the “open state” to the “closed state”. It is worth noting that the positively charged lysine-arginine (KR) cluster is responsible for regulating the conformation of HMGA1a through electrostatic interaction with the phosphorylated acidic tail. In vitro, dephosphorylation increases the affinity of nuclear HMG-I(Y) (current name HMGA1) to DNA. Serine-threonine kinase homologous domain interaction protein kinase 2 (HIPK2) is involved in regulating important cellular functions during development. It acts as a signal integrator for various stress signals and as a regulator of transcription factors and cofactors. HIPK2 phosphorylates Ser-35, Thr-52, Thr-77, Thr-41 and Thr-66 of HMGA1. HIPK2-mediated phosphorylation reduces the DNA-binding affinity of HMGA1 but increases it in the absence of ATP [58–60]. IL-4 induces serine phosphorylation of HMGA1 in B lymphocytes through CK2, which decreases the binding of recombinant HMGA1 to DNA. This phosphorylation is inhibited by rapamycin [61, 62]. Protein kinase CK2 catalyzes the constitutive phosphorylation of acidic C-terminal Ser98, Ser101, and Ser102 of HMGA1 in vivo and in vitro [63–65]. HMGA1 is also a substrate for cdc2 kinase. The A-T hook of mouse HMGA1 is specifically phosphorylated by purified mammalian cdc2 kinase in vitro, and the same site is phosphorylated in vivo in metaphase-arrested cells. The DNA-binding affinity of short synthetic binding domain peptides, when phosphorylated by cdc2 kinase in vitro, was significantly lower than that of the unphosphorylated peptides. Additionally, Thr52 and Thr77 in HMGA1 are phosphorylated in vivo in a cell cycle-dependent manner and are also phosphorylated by cdc2 kinase in vitro [63, 66–69]. Phosphorylation of Thr20, Ser43, and Ser63 in HMGA1 is catalyzed by protein kinase C-α (PKCα) both in vivo and in vitro [70]. Phosphorylation of various regions of the HMGA1 protein reduces its binding affinity to DNA to different degrees.In conclusion, these phosphorylation modifications of HMGA1, by altering its conception to a closed state, reduce its affinity for DNA and inhibit its binding to DNA.
In addition, IKBKE (Inhibitor of Nuclear Factor Kappa-B Kinase Subunit Epsilon) is a key oncogenic protein involved in various tumors. It promotes tumor growth, proliferation, invasion, and drug resistance, playing a crucial role in the initiation and progression of malignant tumors. IKBKE can phosphorylate Ser-36 and/or Ser-44 of HMGA1, inhibiting its degradation and regulating its nuclear translocation [25]. HMGA1 also serves as a substrate for ATM. It interacts with ATM and is phosphorylated as part of the ATM pathway in response to DNA damage. Reciprocally, HMGA1 regulates ATM expression, and ATM kinase activity induced by DNA damages enhances HMGA1-dependent activation of the ATM promoter. Inhibition of HMGA1 expression in mouse embryonic fibroblasts and cancer cells markedly reduces ATM levels, weakening DDR of the cell and increasing the sensitivity of the cell to DNA damages [71–73] (Fig. 1). Here, the significance of phosphorylation of HMGA1 in maintaining DNA stability is emphasized.

PARylation of HMGA1
HMGA1 undergoes ADP ribosylation, a process often triggered by DNA damage. In response to DNA damage, adenosine diphosphate (ADP) ribosylation—including PARylation and mono(ADP-ribosyl)ation (MARylation)—is rapidly catalyzed at the site of the DNA damage by poly(ADP-ribosyl) polymerase (PARP). These modifications are recognized by ADP ribose (ADPR)-binding proteins. Since multiple DNA damage repair proteins contain ADPR-binding motifs, these “readers” play an important role in promoting DNA damage repair. As such, ADP ribosylation is one of the earliest signals of DNA damage and mediates the initial wave of the DNA damage response [74–76].
Giancotti et al. identified ADP glycosylation in the HMGI proteins (HMGA1 and HMGA2) isolated from the nuclei of mouse Lewis lung cancer cells [77]. Recently we demonstrated that HMGA1 is modified by PARP1 through PARylation [18]. PARylation is a post-translational modification where proteins are modified by linear or branched chains of ADP-ribose units derived from NAD+. The major enzyme responsible for ADP-ribose polymerase activity during DNA damage is PARP1, a highly conserved multifunctional enzyme found in eukaryotic cells. The activity of PARP1 is stimulated by various activators, including DNA damage. We recently showed that HMGA1 interacts with PARP1 upon DNA damage, during which PARylation occurs at the 47E and 50E residues of HMGA1. This modification enhances the function of HMGA1 and promotes the formation of the DNA-PK complex, facilitating DNA repair [12] (Fig. 1). Table 2.

Other modifications of HMGA1

Acetylation of HMGA1
In the context of gene expression regulation, the dynamic control of interferon-β (IFN-β) gene expression requires the assembly and disassembly of enhancers. These enhancers are higher-order nucleoprotein complexes formed in response to viral infections. They activate transcription by recruiting histone acetyltransferase proteins such as CREB-binding protein (CBP) and p300/CBP-associated factor (PCAF)/GCN5. In addition to modifying histones, these acetyltransferases also acetylate HMGA1, a structural component necessary for enhancer assembly [78–80].
Acetylation is a common post-translational modification of HMGA1. It occurs across all AT-hooks of the HMGA1a protein, with the region between the second and third AT-hooks being more prone to acetylation. Five specific lysine residues in HMGA1a—Lys-14, Lys-65, Lys-66, Lys-71, and Lys-73—are acetylated by the acetyltransferases p300 and PCAF. These two enzymes exhibit distinct site preferences: p300 preferentially acetylates Lys-64, ~Lys-70 > Lys-66 > Lys-14, ~Lys-73, whereas PCAF selectivity follows the order Lys-70, ~Lys-73 > Lys-64, ~Lys-66 > Lys-14. The acetylation pattern of HMGA1b is very similar to that of HMGA1a. Furthermore, C-terminal phosphorylation of HMGA1 does not affect its acetylation by p300 or PCAF in vitro. These five lysine residues are also acetylated in vivo, with Lys-64, Lys-66, and Lys-70 in HMGA1a showing higher acetylation levels than Lys-14 and Lys-73 [81, 82]. Furthermore, acetylation at two key sites leads to different biological outcomes: acetylation of Lys-64 disrupts enhancer/promoter stability, whereas acetylation of Lys-70 enhances interferon-β gene transcription by stabilizing the enhancer/promoter complex and preventing HMGA1a acetylation by CBP [78, 82].

Methylation of HMGA1
Protein methylation, particularly on lysine and arginine residues, adds a layer of complexity to signal transduction. In contrast to histones, where lysine methylation is predominant, arginine methylation is particularly relevant for HMGA proteins. Arginine methylation of HMGA1 is involved in signal transduction, RNA metabolism, transcriptional regulation, and DNA repair. This modification is catalyzed by protein arginine methyltransferases (PRMTs) [64].
PRMT1 and PRMT3 primarily methylate arginine residues within the first AT-hook of HMGA1, whereas PRMT6 primarily targets residues in the second AT-hook. Tandem mass spectrometry has shown that PRMT1 and PRMT3 methylate Arg-25 and Arg-23, respectively, while PRMT6 methylates Arg-57 and Arg-59 of HMGA1. The binding of HMGA1 to AT-rich double-stranded DNA, but not to GC-rich duplex DNA, significantly inhibits its methylation by all PRMTs [64, 83]. Furthermore, constitutive phosphorylation of the HMGA1 C-terminal region by protein kinase CK2 does not significantly affect its methylation in vitro [65].
Studies have shown that monomethylation of Arg-25 in HMGA1a is associated with the execution of apoptosis in cancer cells. Additionally, dimethylation of both arginine and lysine residues has been observed in cultured human breast cancer cells with varying metastatic potential. Arg-25, located in the first DNA-binding AT-hook domain, can be both monomethylated and dimethylated, with both symmetric and asymmetric dimethylation forms detected. Interestingly, the closely related HMGA1b protein does not undergo methylation [84]. Furthermore, increased HMGA1a methylation is a hallmark of apoptosis in leukemia cells. Specifically, methylation of the first AT-hook (Arg-25) occurs during apoptosis and appears to coincide with protein dephosphorylation. This coupling of methylation and dephosphorylation is considered part of a broader set of modifications—including phosphorylation, acetylation, and methylation itself—that collectively regulate the formation of protein complexes responsible for chromatin remodeling and gene activity during apoptosis.

Sumoylation and ubiquitination of HMGA1
Post-translational modifications (PTMs) are enzyme-driven processes that impact nearly the entire cellular proteome, influencing the fate of target proteins and, consequently, cellular activity. SUMOylation and NEDDylation are ubiquitin-like multi-enzyme processes involving the attachment of SUMO (Small Ubiquitin-like Modifier) and NEDD8 to specific target protein residues, respectively, thereby regulating their function. Dysregulation of SUMOylation and NEDDylation can affect various aspects of tumor transformation and evolution, including epithelial-mesenchymal transition (EMT), adaptation to hypoxia, tumor suppressor expression and function, oncogenic mediator activity, and drug resistance [85–87].
HMGA1 interacts with the SUMO E2 conjugating enzyme Ubc9, which facilitates SUMOylation. The Ubc9 interaction domain of HMGA1 consists of two regions: a proline-rich region near the N-terminus and an extremely acidic region at the C-terminus. Interestingly, Ubc9-mediated modulation of HMGA1 function does not appear to require SUMOylation itself. Instead, Ubc9 can act as both a positive and negative regulator of cell proliferation and transformation through non-SUMO-dependent interactions with HMGA1 [88].
Studies have shown that USP7 and HMGA1 coexist in a complex. HMGA1 binds to USP7, thereby stabilizing CCF. However, it remains unknown whether USP7 affects the ubiquitination level of HMGA1 [89]. Additionally, glucose-regulated protein 75 (GRP75), a heat shock protein belonging to the HSP70 family [90], inhibits the ubiquitination-mediated degradation of HMGA1 by directly binding to it, leading to HMGA1 upregulation in lung adenocarcinoma (LUAD) cells.

The role of HMGA1 in genome stability

HMGA1 in DNA repair and replication
HMGA1 is a highly connected node in the nuclear molecular network, and its involvement in cancer development is pivotal due to its ability to simultaneously exert multiple carcinogenic effects on cells [91, 92]. These effects range from modifications in chromatin structure and facilitation in gene expression to direct functional regulations in critical cellular proteins. Studies have shown that HMGA1 plays a significant role in DNA damage repair by directly or indirectly regulating DNA repair proteins, contributing to multiple DNA repair pathways, and maintaining genome integrity.
Ataxia-telangiectasia mutated (ATM) is central to a network of proteins phosphorylated in response to DNA damage. These proteins are involved in signaling pathways that maintain genome stability and minimize disease risk by controlling cell cycle checkpoints, initiating DNA repair, and regulating gene expression. ATM kinase can be activated by various stimuli, including oxidative stress. HMGA1 is a substrate of ATM, with a specific SQ motif identified on HMGA1 that is efficiently phosphorylated by ATM both in vitro and in vivo. HMGA1 co-localizes with the activated form of ATM (pho-ATM S1981) [71, 73]. Inhibition of HMGA1 expression in mouse embryonic fibroblasts and cancer cells significantly reduces ATM levels, impairs the DNA damage response, and increases sensitivity to DNA-damaging agents [72]. Similarly, inhibiting HMGA1 expression in thyroid cancer cells decreases ATM and enhances the sensitivity of cells to DNA-damaging agents [93] (Fig. 2).
Additionally, HMGA1 enhances DNA ligase IV (LIG4) activity. Histone H1 has dual activity in terms of DNA ligation efficiency. At low concentrations, it enhances LIG4 activity by facilitating the bridging of DNA ends. Conversely, at higher concentrations, histone H1 acts as a blocking factor to promote aggregate formation and inhibit LIG4 activity. HMGA1 competitively binds to LIG4 with H1, reducing the inhibitory effect of histone H1 on LIG4 activity [36]. In breast cancer cells with high HMGA1 expression, the cells recover more quickly after induced DNA double-strand breaks, a feature associated with higher survival rates (Fig. 2).
The latest evidence indicates that HMGA1 promotes non-homologous recombination repair and inhibits intracellular DNA damage. HMGA1 interacts with PARP1 and is recruited to sites of DNA damage, where it undergoes PARylation. This modification facilitates the assembly of Ku70-Ku80 complexes at the damage site and activates DNA-PKcs, promoting non-homologous end joining DNA repair. In BRCA1/2-deficient cell lines, HMGA1 inhibition decreases cancer cell survival and suppresses cancer cell growth. Conversely, HMGA1 overexpression enhances the resistance of esophageal cancer cells to olaparib, contributing to cancer progression [25]. These findings establish a connection between HMGA1 and NHEJ-mediated DNA repair mechanisms (Fig. 2). Additionally, HMGA1 has been implicated in homologous recombination (HR) repair [94]. HMGA1 facilitates the HR process, supporting the repair of DNA double-strand breaks. Studies in Arabidopsis thaliana identified a telomere-interacting protein, HON4 (renamed GH1-HMGA1), as a high-mobility histone A (HMGA) protein. As a telomere-binding factor, GH1-HMGA1 binds chromatin in vivo. Mutations in HMGA1 are associated with defects in homologous recombination, underscoring its critical role in maintaining genomic stability.
Research has demonstrated that HMGA1a/b and HMGA2 possess intrinsic dRP (deoxyribose phosphate) and AP (apurinic/apyrimidinic) site cleavage activities [95]. The lysine and arginine residues in their AT-hook DNA-binding domains function as nucleophilic reagents, enabling this activity. In cancer cells, HMGA1 can be covalently captured at abasic sites in the genome. Its associated lyase activity enhances cellular resistance to DNA damage targeted by the base excision repair (BER) pathway. This protective effect is directly correlated with HMGA1 expression levels. Furthermore, the interaction between human AP endonuclease 1 (APE1) and HMGA1 facilitates the incorporation of HMGA1 into the BER pathway in cancer cells. This interaction underscores HMGA1’s role in enhancing DNA repair processes, contributing to cancer cell survival and resistance to DNA damage (Fig. 3).

HMGA1 plays a critical role in supporting DNA replication. By promoting the transcriptional upregulation of TKT, HMGA1 enhances the pentose phosphate pathway (PPP) [12], providing nucleotide precursors essential for DNA repair and replication. This activity supports the replication and proliferation of cancer cells. Additionally, lncRNA IGF2-AS has been shown to promote apoptosis in endothelial progenitor cells of sepsis patients by mediating HMGA1 regulation of nucleotide metabolism [96]. Together, these findings highlight the unexpected and multifaceted role of HMGA1 in DNA repair and replication. While most of the reports demonstrated the role of HMGA1 in DNA repairs, other studies showed that HMGA1 could impair DNA damage repair. High levels of HMGA1 are associated with defects in NER. Specifically, cells overexpressing HMGA1 exhibit impaired gene-specific NER following exposure to DNA-damaging agents. Reducing intracellular HMGA1 levels has been shown to improve NER efficiency.One mechanism underlying this impairment is the downregulation of xeroderma pigmentosa Complementary Group A(XPA), a key protein involved in NER [97]. HMGA1 inhibits XPA expression, resulting in increased sensitivity to ultraviolet (UV) light [98](Fig. 3).
HMGA1 also affects mitochondrial DNA (mtDNA) stability. HMGA1translocates from the nucleus to the mitochondria, where it binds to the D-loop control region of mtDNA. Changes in mtDNA levels and mitochondrial mass are inversely correlated with HMGA1 concentration, suggesting that HMGA1 plays a regulatory role in mtDNA. Overexpression of HMGA1 increases reactive oxygen species (ROS) levels in cells, reducing the efficiency of mtDNA repair after oxidative damage [99, 100]. This dual role of HMGA1 in impairing NER and destabilizing mtDNA highlights its complex influence on genome integrity, with significant implications for cancer development and progression (Fig. 4).

Together, these findings have important implications for the role of HMGA1 in mutation accumulation and genome instability, which are closely associated with various types of human cancer.

HMGA1 in chromatin remodeling
Chromatin structure creates steric hindrance that prevents the free entry of transcription factors and coactivators into DNA [101]. This hindrance is overcome by epigenetic mechanisms, ultimately leading to chromatin opening. Chromatin accessibility is a crucial factor in regulating gene expression in cancer cells. HMGA1 protein acts as a adaptor histone antagonist, weaken the affinity between histone and DNA, relax chromatin, and thus enhance transcriptional activity. HMGA1 can promote the transcription ability of ATF4,SP1,SREBP1 and other transcription factors to target genes(Fig. 5).

The various conformations that chromatin adopts are closely related to post-translational modifications (PTMs) of histone tails protruding from nucleosomes, the main scaffolding structure of DNA. Histone lysine acetylation plays a key role in chromatin regulation and gene expression in eukaryotic cells. Generally, histone acetylation is associated with an active chromatin state, while histone deacetylation inhibits gene expression [102–105].
Central carbon metabolic enzymes are specific targets, and most glycolytic and tricarboxylic acid (TCA) cycle enzymes in various organisms, as well as enzymes involved in photosynthesis in plants, undergo acetylation. Their acetylated states influence enzyme activity and regulate metabolic flux through corresponding pathways [106, 107]. Important metabolites, such as acetyl-CoA and NAD, act as substrates or cofactors in the processes of lysine acetylation and deacetylation, respectively. Previous studies have shown that HMGA1 supports tumor development by promoting glycolysis and fatty acid synthesis in cancer cells. The products of glycolysis and fat oxidation promote the production of acetyl-CoA [12, 27], which could be associated with increased intracellular acetylation, including histone acetylation, and supports chromatin opening. HMGA1 DNA binds through three AT hook motifs, resulting in an open chromatin structure that subsequently leads to changes in gene expression(Fig. 5).

HMGA1 in chromosome stability
First proposed by Theodor Boveri in 1902, abnormalities in chromatin structure and function are well-known markers of cancer. In fact, abnormal nuclear structure is a key feature that differentiates cancer cells from normal cells histologically [108].
The spindle assembly checkpoint (SAC) is a fundamental signal transduction mechanism in higher organisms, ensuring the proper distribution of the genome during cell division. This checkpoint delays mitosis until all chromosomes form stable bipolar attachments to the spindle microtubules. The core components of SAC are highly conserved and include several kinases such as Bub1, BubR1 (also known as Bub1b), Mps1 (Ttk), and Aurora B. These components collaborate with other proteins (Mad1, Mad2, Bub3, Cdc20) to form a centromeric protein complex that assembles at the centromeric region of the chromosome. This complex acts as a platform and signaling hub to coordinate chromosome attachment, SAC activity, and cell cycle progression from the middle to late stages of mitosis [109].
Dr. Pierantoni and colleagues have shown that HMGA1 binds to the promoter regions of SAC genes, including Ttk, Mad2l1, Bub1, and Bub1b, and upregulates their expression. Depletion of HMGA1 induces downregulation of SAC, leading to mitotic defects. Disturbance of SAC contributes to chromosomal instability in cells [109]. Subsequent studies demonstrated that HMGA1 overexpression in colorectal cancer correlates with overexpression of SAC genes, which could also contribute to chromosomal instability (CIN). Findings in these studies might seem contradictory and regulation of SAC expression by HMGA1 is crucial for maintaining genome stability in embryonic cells. However, overexpression of HMGA1, a hallmark of malignant tumors, contributes to cancer progression by inducing chromosomal instability, which ultimately leads to more advanced cancer stages. These two pathways are essential for normal development but are disrupted in carcinogenesis [108–110].
A common and undisputed feature of eukaryotic cells is that their genome is divided into multiple chromosomes and encapsulated within a single nucleus [111]. Yamashita et al. report on how structures called chromocenters help maintain the genome inside its nuclear shell between cell divisions. Chromocenters are found in a wide range of organisms and consist of large amounts of heterochromatin—dense clusters of DNA and proteins—that come together during interphase. A chromocenter contains the “pericentric region” of DNA and is composed of highly repetitive, non-coding “satellite” DNA sequences. The pericentromere satellite DNA is a key component of chromosomes, enabling all chromosomes to be packed into a single nucleus [112]. Poly AT-hooked proteins can bind to satellite DNAs around the centromeres, and are present in the interphase chromocenters. Jagannathan et al. conducted experiments in fruit fly and mouse cells, showing that chromocenters are destroyed when polyAT-hooked proteins are absent, which results in micronucleus formation [111, 113].These studies suggest that HMGA1 may maintain chromocenters stability and protect the cell nucleus (Fig. 6). Chromosomal instability has complex consequences, including the loss or amplification of driver genes, focal rearrangement, extrachromosomal DNA, micronucleus formation and the activation of innate immune signals. This is related to disease stage, metastasis, poor prognosis and treatment resistance. Studies have shown that overexpression of HMGA1 in tumors promotes DNA repair and leads to chemotherapy resistance in tumors [25, 31]. The above results suggest that HMGA1 may promote tumor development by maintaining chromatin stability.

HMGA1 and cell death
DNA damage repair is crucial for maintaining genome stability, with repair factors and cell cycle regulation proteins forming a system that upholds genomic integrity. The genome is constantly exposed to damages from both endogenous and exogenous factors. Persistent DNA damage leads to increased genomic instability and activates the DDR, which may eventually inhibit cell cycle progression or induce cell death [114]. Cell death can occur through various mechanisms, including autophagy, apoptosis, ferroptosis, pyroptosis, and necrosis. In multicellular organisms, genetically programmed cell death is an essential component of homeostasis. Previous studies have shown that HMGA1 is associated with various forms of cell death and affects tumorigenesis and development by regulating cell death pathways. We have summarized the previously reported research results on HMGA1’s inhibition of cell death. Although there is no direct evidence indicating that HMGA1’s inhibition of cell death is related to genomic stability, we hope that our upcoming summary can provide ideas and evidence for this direction.

Autophagy
DNA damage response (DDR) involves DNA repair, cell cycle regulation and cell death, but autophagy is also believed to play a role in DDR. Autophagy can be activated in response to DNA damage agents, but the exact mechanism of this activation is not yet fully understood. HMGA1 depletion has been shown to increase autophagy. For example, downregulation of HMGA1 induces autophagy through the miR-221/TP53INP1/p-ERK axis, inhibiting the proliferation, migration, and invasion of breast cancer (BC) cells [33]. Similarly, HMGA1 depletion impairs cancer cell viability by inhibiting the mTOR pathway and upregulating ULK1 transcription levels [34]. Additionally, RNF157-AS1 binds to EZH2 and HMGA1 proteins and inhibits the expression of DIRAS3 and ULK1. ULK1 and DIRAS3, as regulators of autophagy initiation, play crucial roles in the autophagy process [115]. In addition, functional studies using endogenous HMGA1 gene knock-down have demonstrated that inhibition of HMGA1 signaling accelerates nerve cell death, at least in part by exacerbating MPP(+)-reduced autophagy flux and partially blockingthe end-stage autophagy process [12, 86, 116] (Fig. 7). Evidence indicates that mTORC1 inhibits autophagy through the phosphorylation of the ULK1/2-Atg13-FIP200 complex, thereby preventing the maturation of the pre-autophagosome structure. When DNA damage occurs, it is recognized by some proteins or their complexes, such as poly (ADP) ribose polymerase 1 (PARP-1), Mre11-Rad50-Nbs1 (MRN) complex or FOXO3, which activate the repressor of mTORC1. SQSTM1/p62 is one of the proteins that regulate its level through autophagy degradation. Knockdown of FIP200 inhibits autophagy, leading to upregulation of SQSTM1/p62, enhancing DNA damage and reducing the efficiency of damage repair. These results suggest that HMGA1 may promote DNA repair, inhibit autophagy and facilitate tumor development through this relationship.

Apoptosis
It is well known that DNA damage can lead to cell apoptosis. Apoptosis is a classic form of programmed cell death that occurs under various physiological and pathological conditions. HMGA1, as a dynamic regulatory factor for gene transcription and chromatin remodeling, plays a significant role in the pathological processes of many cardiovascular diseases. Evidence indicates that HMGA1 plays a significant role in inhibiting apoptosis and promoting tumor development.HMGA1 is highly expressed in lung adenocarcinoma (LUAD) and associated with the activation of glycolytic pathway in the tumor. Silencing HMGA1 significantly hinders cell proliferation and glycolysis while promoting apoptosis. Transcription factor AP-2 alpha (TFAP2A) enhances glycolysis, cell proliferation, and inhibits apoptosis in LUAD cells by stimulating HMGA1 expression. Therefore, the TFAP2A/HMGA1 axis could be a potential therapeutic target for LUAD [117]. Some studies have pointed out that HMGA1 promotes the progression of esophageal squamous cell carcinoma by increasing the upregulation of the pentose phosphate pathway mediated by TKT. Among them, the author found that HMGA1 knockdown inhibits PPP by down-regulating TKT, resulting in a reduction of nucleotides in ESCC cells and an increase in DNA damage within the cells. Overexpression of HMGA1 upregulates PPP and promotes the survival of ESCC cells by activating TKT. These studies have linked HMGA to apoptosis and DNA damage, suggesting some kind of connection between them. In addition, p53, as an apoptotic protein, is also associated with HMGA1 and DNA damage.
P53 is a tumor suppressor gene and is also associated with HMGA1 and DNA damage. p53 often mutates in cancer. It interacts with anti-apoptotic proteins BCL-xL and Bcl-2, altering mitochondrial membrane permeability and mediating apoptosis. Studies have shown that HMGA1 interacts with P53, and the c-terminal oligomeric domain of p53 family members is necessary for direct interaction with HMGA1. Down-regulation of HMGA1 can enhance the transcriptional activity of p53, TAp63alpha and TAp73alpha, thereby increasing apoptosis.The inhibition of HMGA1 expression in thyroid cancer cells leads to an increase in p53 oligomerization in response to the DNA damage agent doxorubicin. In addition, the p53-HMGA1 interaction leads to a decrease in DNA binding activity, affecting the transcriptional regulatory function of HMGA1 [118] (Fig. 7).These pieces of evidence suggest that HMGA’s inhibition of cell death may be related to the response to DNA damage.

Ferroptosis
Ferroptosis is a novel form of iron-dependent cell death characterized by lipid peroxidation. Although the significance of ferroptosis and its disease relevance are being recognized, there are still many unknowns regarding its interaction with other biological processes and pathways. Recently, several studies have identified the intricate interactions among ferroptosis, ionizing radiation (IR), ATM (ataxia-telangiectasia mutation)/ATR (ATM and RAD3-related), and tumor suppressor p53, suggesting that DNA damage response (DDR) is involved in iron-related cell death. The latest evidence indicates that HMGA1 promotes the development of esophageal cancer by inhibiting ferroptosis. HMGA1 plays a key role in chemotherapy resistance in ESCC by inhibiting ferroptosis [12]. HMGA1 enhances the recruitment and binding of the transcription factor ATF4 to the promoter of SLC7A11, which promotes the transcription of this gene, acting as a suppressor of ferroptosis. Depletion of HMGA1 promotes ferroptosis and restores the sensitivity of ESCC cells to chemotherapy both in vitro and in vivo.These results also suggest the choice made by HMGA1 between maintaining genomic stability and cell death. Emerging evidence also suggests a link between HMGA1 and pyroptosis. In sepsis, both lncRNA IGF2-AS and HMGA1 are significantly upregulated. The lncRNA IGF2-AS promotes pyroptosis in endothelial progenitor cells from septic patients by modulating HMGA1, thereby regulating nucleotide metabolism [96]. This demonstrates that lncRNA IGF2-AS facilitates pyroptosis through its regulation of HMGA1. However, the precise molecular mechanisms by which HMGA1 regulates pyroptosis remain unclear, and whether its pro-pyroptotic effect is associated with DNA damage requires further investigation [96] (Fig. 7).

Strategies for inhibiting HMGA1
At present, there are several strategies targeting inhibition of HMGA1. These include molecules that accumulate at AT sequences to compete with HMGA1 to bind to DNA, compounds that bind AT-rich sequences to HMGA1, highly specific HMGA1-binding molecules, cross-linking complexes, and agents that inhibit HMGA1 expression and transcription. These strategies offer promising approaches for inhibiting the function of HMGA1 in cancer and other diseases, providing potential clinical treatment options. Table 3.

AT binding compounds
HMGA1 is a structural transcription factor that binds to small grooves in AT-rich DNA regions through AT-hook to form transcription factor complexes (“ enhancers “), which are involved in a variety of diseases. AT-rich regions of DNA surround transcription factor binding sites in genes critical to inflammatory responses. For example, HMGA1 is crucial in promoting the binding of nuclear factor (NF)-κB to human E-selectin promoters [119]. Small groove-binding agents (MGBs), such as digamycin A (Dist A), interferes transcription factors binding to AT-rich regions of DNA in a sequence- and conformation-specific manner. This disrupts the interaction between transcription factors and AT-rich DNA sequences [120]. HMGA1 is one of the few structural transcription factors whose binding can be inhibited by small groove binders (MGBs). Su et al. screened and obtained several compounds that strongly inhibit HMGA2-DNA interactions, including suramin, using a miniaturized, automated AlphaScreen ultra-high throughput assay. Suramin binds to the “AT-hook” DNA-binding motifs, preventing HMGA2 from interacting with small grooves in AT-rich DNA sequences. Notably, suramin also inhibits the interaction between HMGA1 and DNA [121, 122].
Actinomycin D, an antibiotic and anti-tumor drug, selectively binds and stabilizes single-stranded DNA capable of adopting a hairpin conformation. This binding mechanism is linked to the drug’s ability to inhibit HIV reverse transcriptase transcription from a single-stranded DNA template. Netropsin effectively competes with two AT-hook motifs of HMGA2 for binding to the AT-rich NOS1 promoter sequence. Furthermore, direct molecular interactions between netropsin and A/T base pairs within the NOS2 promoter, where HMGA1 binds, were observed [123] (Fig. 8).
Trabectedin functions primarily by intercalating into the minor groove of DNA, forming trabectedin-DNA adducts that disrupt the transcription of oncogenes. Studies have shown that trabectedin suppresses both mRNA and protein levels of HMGA in liposarcoma [124, 125]. Notably, HMGA1 itself binds to the DNA minor groove to facilitate enhanceosome assembly and gene transcription. Research has shown that trabectedin exerts its function by competing with HMGA proteins for the minor groove in DNA, displacing them and ultimately inhibiting the regulatory effect of HMGA proteins on transcriptional activity. Additionally, it has been demonstrated that E2F1 interacts with the 193-bp region of the HMGA1 promoter, facilitating its transcription. Trabectedin inhibits the binding of HMGA1 to E2F1, thereby suppressing the transcription of HMGA1 [124, 126, 127] (Fig. 8).

Highly bound molecules
Designing and synthesizing a small molecule compound highly bound to HMGA1 is a potential means to inhibit HMGA1, with the aim of suppressing the function of HMGA1 by binding to it through competitive performance. Recombinant adenovirus (Ad) vectors are widely utilized for gene delivery, cancer therapy, and as vaccines expressing antigenic peptides [128, 129]. Over 400 gene therapy trials have been conducted or are ongoing using Ad vectors. Ad5, an unenveloped virus with a double-stranded DNA genome, features an icosahedral capsid composed mainly of pentameric and hexagonal proteins. The versatility of adenovirus vectors in accommodating large foreign DNA sequences and effectively infecting both dividing and non-dividing cells makes them an excellent tool for gene therapy and cancer treatment. Additionally, adenoviruses can be produced as high-titer viral reservoirs, with their dsDNA genomes remaining unintegrated into host cell chromosomes. Human pancreatic cancer cells were transfected with DNA aptamers modified with thiophosphate, containing HMGA bait binding sites, which led to a decrease in cancer cell viability following chemotherapy. Hassan et al. designed a synthetic HMGA1 decoy hyperbinding site consisting of six copies of a single HMGA binding site. A replication-deficient adenovirus vector, called AdEasy-HMGA-6, was used to deliver these decoy AdEasy-HMGA-6 hyperbinding sites into the cell nucleus, where they isolated the overexpressed HMGA protein. The AdEasy-HMGA-6 hyperbinding sites acted as bait, attracting excessive HMGA binding in the cancer cell nuclei and disrupting the carcinogenic effects caused by HMGA-related gene expression dysregulation and chemotherapy resistance. Infection with AdEasy-HMGA-6 in pancreatic and liver cancer cell lines significantly reduced cancer cell viability and increased sensitivity to the chemotherapy drug gemcitabine [130]. This viral vector transfer did not trigger a heightened immune response but did cause some liver damage (Fig. 8).

Crosslinked complex
DNA transstrand binders are considered among the most effective chemotherapy drugs due to their powerful anti-tumor and anti-bacterial properties. These drugs work by forming covalent bonds between the two strands of double-stranded DNA, blocking critical biological processes such as transcription and DNA replication. The presence of two active sites in these molecules suggests additional pathways that may contribute to their biological activity, such as monoalkylated biomacromolecules and nucleic acid-protein crosslinks. FR900482 and FR66979 are anti-tumor antibiotics isolated from the fermentation of Streptomyces shandasanensis 6897 by Fujisawa Pharmaceutical [131, 132]. Clinical candidates FK973 and FK317 are semi-synthetic derivatives of FR900482, both demonstrating promising anti-tumor activity in human clinical trials [133]. Earlier studies by Fujisawa Co. revealed that both FR900482 and FK973 influence the formation of DNA interstrand crosslinks and DNA-protein crosslinks in L1210 cells [134–136]. These compounds also cross-link HMGA1 proteins in small DNA grooves, inhibiting the interaction of these cancer-related proteins with DNA in living cells. FK317 is currently undergoing advanced clinical trials in Japan and is expected to replace the widely used anti-tumor drug mitomycin C (MMC) (Fig. 8).

Inhibit the expression of HMGA1
HMGA1 is overexpressed in many human malignancies but is almost absent in healthy adults, making it a potential “tumor marker.” Additionally, HMGA1 is implicated in several diseases such as myocarditis, aging, and diabetes. Therefore, inhibiting the expression of HMGA1 holds significant therapeutic potential. One approach is to inhibit the transcription of HMGA1, thereby reducing its expression.
Akhter et al. achieved this by using two triplex-forming oligonucleotides (TFOs), TFO1 and TFO2, which targeted the − 284 to −304 and − 2800 to −2826 regions of the HMGA1 promoter, respectively. Various biophysical and thermodynamic techniques were employed to assess the stability of these DNA triplets. Both TFOs downregulated HMGA1 expression at the mRNA and protein levels and induced apoptotic cell death in HeLa cells. Thus, TFO-mediated inhibition of HMGA1 expression could be a promising strategy for developing novel therapeutic drugs [137].
Scala et al. generated an adenovirus carrying the HMGA1 gene in the antisense direction (Ad Yas-GFP), which caused the death of three human pancreatic cancer cell lines (PANC1, Hs766T, and PSN1) by downregulating HMGA1 expression. Pretreating PANC1 and PSN1 cells with Ad Yas-GFP reduced the ability of these cells to form xenograft tumors in nude mice. Additionally, injecting Ad Yas virus into thymus-free mice inhibited the growth of xenograft tumors induced by thyroid undifferentiated cancer cells [138]. Furthermore, flavonopyridinol has been reported to inhibit HMGA1 gene expression, though the specific mechanism remains unclear [139].
Adriamycin (ADM), the most potent member of the glycoside anthracycline class of antibiotics, is widely used in chemotherapy due to its effectiveness against various human malignancies. Its antitumor activity is primarily attributed to its ability to interact with DNA, inhibiting DNA replication and RNA transcription, or by inhibiting topoisomerase II. Some studies indicate that ADM binds to the HMGA1 gene promoter region (−304 to −284) and 21RY, leading to a reduction in both mRNA and protein levels of HMGA1 [140, 141] (Fig. 8).

RNAs targeting HMGA1
Various long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and the two pseudogenes of HMGA1, P6 and P7, interfere with HMGA1 expression by competing with its endogenous RNA. These RNA molecules serve as potential regulators to inhibit cancer progression. For instance, miR-24-3p promotes myoblast differentiation and skeletal muscle regeneration by directly targeting HMGA1, and modulating its activity along with its direct downstream target, differentiation inhibitor 3 (ID3) [142, 143].The use of specific miR-26a oligonucleotides decrease HMGA1 expression and inhibit the metastasis of pancreatic cancer cells [143].
Similarly, miR-195 binds to the 3’ untranslated region (UTR) of HMGA1, inhibiting its expression [10]. Additionally, miR-195 interacts with the 3’ untranslated region of HMGA1 mRNA, downregulating HMGA1 expression at the protein level. Similarly, HMGA1 has been confirmed as a direct target of miR-625. miR-625 mimics induce a decrease in HMGA1 mRNA and protein expression, while miR-625 inhibitors increase HMGA1 levels. Let-7, one of the first discovered miRNAs, may also target HMGA1, with let-7i-5p being one of its potential regulators [144]. The expression of HMGA1 protein and mRNA was downregulated in bladder cancer cells transfected with let-7i mimics. Upregulation of let-7i inhibited the proliferation and migration of these cell lines by targeting HMGA1. These findings suggest that let-7i may serve as a potential therapeutic target for bladder cancer. HMGA1 is also a target gene of miR-26a-5p, which can alleviate CME-induced myocardial injury by inhibiting HMGA1 expression [145].
Endogenous and exogenous tumor-associated microRNAs are emerging as promising biomarkers and therapeutic agents for cancer. Zhang et al. proposed a miRNA self-responsive drug delivery system (miR-SR DDS), designed to link both endogenous and exogenous miRNAs for intelligent response and collaborative drug delivery. The miR-SR DDS comprises DNA-miRNA hybrids of let-7a and complementary DNA of miR-155, packaged within exosomes. In response to the overexpression of miR-155 in breast cancer cells, the hybrid breaks down, releasing complementary DNA of let-7a and miR-155 [146]. This process inhibits HMGA1 expression and alleviates SOX1 inhibition, respectively. The study shows that the Wnt/β-catenin signaling pathway, regulated by dual-target genes, inhibits the growth, migration, and invasion of breast cancer cells. The concept and successful implementation of miR-SR DDS provide a valuable reference for the development of miRNA-based drugs.
Studies have shown that HMGA1 is a downstream target of hsa-miR-765. Fluvastatin drives hsa-miR-765 expression to inhibit prostate cancer cell growth by blocking the cell cycle during the G2/M transition. It may also suppress cell migration and invasion by reducing the formation of filopodia and stress fibers, demonstrating significant tumor-inhibitory effects. Moreover, fulvestrant enhances the expression of hsa-miR-765 by recruiting estrogen receptor beta (ERβ) to the 5’ regulatory region of hsa-miR-765 [147]. Both anti-estrogen treatments and hsa-miR-765 mimics effectively inhibit HMGA1 protein expression. In prostate cancer samples treated with fulvestrant, hsa-miR-765 levels increase, and HMGA1 expression is almost completely suppressed (Fig. 8).

Prospectives
Recent studies have highlighted the crucial role of HMGA1 in multiple DNA repair pathways—including NHEJ, HR, and base excision repair—emphasizing its contribution to maintaining genomic stability during tumorigenesis and progression. These findings help elucidate the functions of HMGA1 in normal human development, cancer, and other diseases. We propose that HMGA1 promotes cancer development by participating in two key processes driving tumor formation: maintaining genomic stability and regulating cell death. Specifically, HMGA1 prevents genomic instability by enhancing DNA repair—for instance, through the PPP1 pathway to enhance PARP1 function and facilitate nucleotide biosynthesis—while also promoting tumor progression by suppressing cell death. Consequently, elevated HMGA1 expression in tumors may accelerate tumor initiation.
Studies have shown that high HMGA1 expression in esophageal cancer confers resistance to DDP by inhibiting ferroptosis, while its enhancement of PARP1 function also leads to olaparib resistance. Notably, targeted inhibition of HMGA1, combined with administration of DNA-damaging agents such as DDP or olaparib, significantly improves therapeutic efficacy. These findings demonstrate that HMGA1 promotes tumor development by maintaining genomic stability in cancer cells. The synthetic lethality achieved by targeting HMGA1 in the context of chemotherapy-induced DNA damage holds important implications for clinical cancer treatment.
However, several key questions remain unanswered. These include the role of HMGA1 in other forms of regulated cell death, such as cuproptosis and pyroptosis, as well as its involvement in additional DNA repair pathways like MMR. Furthermore, given the widespread overexpression of HMGA1 in various aggressive tumors, the development of effective strategies to specifically target HMGA1 represents a promising therapeutic strategy. Addressing these questions will deepen our understanding of how to effectively target HMGA1 to suppress tumor development.