Research progress on the role and mechanism of circadian clock gene in the occurrence and development of multiple diseases.

1
Introduction
Biological rhythms are widely present in various life activities in nature. They are endogenous rhythmic life activities that organisms have gradually formed during their occurrence and evolution over hundreds of millions of years to adapt to environmental changes, which are similar to the periodic changes of the natural environment. In short, biological rhythms are the core mechanism for organisms to adapt to the environment, achieving dynamic balance between physiology, behavior and the environment through precise time regulation. Biological rhythms include annual rhythms, monthly rhythms and circadian rhythms. Circadian rhythm is an important biological rhythm, which is the inherent 24-hour periodic rhythm in organisms and is maintained by a highly conserved molecular rhythm device - the biological clock (1). The biological clock is an intrinsic time-regulating system that influences the physiology and behavior of organisms by regulating periodic changes in gene expression (2, 3). A variety of physiological functions of organisms, such as sleep-wake cycles, metabolism, endocrine, immunity, body temperature and cognition, as well as the functional operation of various systems, are all precisely regulated by circadian rhythms (4–6).
The central regulatory hub of circadian rhythms resides within the suprachiasmatic nucleus (SCN) of the hypothalamus. Functioning as the “master clock,” the SCN receives photic inputs via the retinohypothalamic tract, thereby achieving synchronization with the Earth’s 24-hour light-dark cycle. Through the secretion of neurotransmitters (e.g., vasoactive intestinal peptide), the SCN orchestrates rhythmicity across peripheral tissues throughout the organism (7). Beyond the SCN, autonomous molecular circadian oscillators are present in most peripheral tissues (such as the liver and lungs), which maintain synchronization with the central clock through neurohumoral signaling (8). At the molecular level, circadian rhythms are driven by a transcription-translation feedback loop (TTFL) consisting of core clock genes, including brain and muscle arnt-like 1 (BMAL1), circadian locomotor output cycles kaput (CLOCK), PER, and cryptochrome (CRY). These genes generate molecular oscillations with a periodicity of approximately 24 hours via time-delayed feedback regulation (9).
The discovery of the PER1 gene, a core circadian clock regulatory gene, can be traced back to homologous studies on the Period gene in Drosophila, making it one of the earliest identified core clock genes (10). As a crucial component of the circadian clock, PER1 not only participates in maintaining normal circadian rhythms but also plays a significant role in the pathogenesis of various diseases (11). In recent years, the roles of PER1 in cancer, cardiovascular diseases, metabolic disorders, neurodegenerative diseases, and immune-related diseases have been gradually unveiled. Its molecular mechanisms involve multiple levels, including cell cycle regulation, metabolic pathway intervention, and immune response modulation, thus emerging as a key target in interdisciplinary research (Figure 1). Starting from the biological functions of PER1, this article reviews its roles, pathophysiological significance, and related molecular mechanisms in cardiovascular diseases, neurodegenerative diseases, metabolic disorders, immune-related diseases, and cancer. Additionally, we distinguished levels of evidence and cross-species conservation of mechanism, aiming to provide new insights and targets for disease prevention and treatment.

2
Biological characteristics and regulatory mechanisms of PER1
2.1
Core components of the circadian negative feedback loop
PER1 is localized on human chromosome 17p13.1 and encodes a nuclear protein containing a PAS domain. As a key component of the TTFL, PER1 works in conjunction with other circadian clock genes to maintain the body’s circadian rhythm. The core of the molecular mechanism underlying the circadian clock is an autonomous oscillatory system composed of TTFL, in which PER proteins, together with CLOCK, BMAL1, and CRY proteins, form a core regulatory network (12, 13). Period circadian regulator serves as a core regulatory factor in the negative feedback loop of the mammalian circadian clock, and together with CLOCK, BMAL1, CRY RAR-related orphan receptors (RORs), and nuclear receptor subfamily 1 group D member 1 (NR1D1), it regulates the circadian rhythmicity of physiological activities in the organism.
As a pair of transcriptional activators, CLOCK and BMAL1 form a CLOCK-BMAL1 heterodimer, which binds to the E-box in the promoter region to activate the transcription of PER and CRY genes. When PER and CRY proteins reach a certain concentration in the cytoplasm, they form a dimer, translocate into the nucleus, and then inhibit the transcriptional activity of the CLOCK-BMAL1 heterodimer. This negative feedback mechanism ensures the timely suppression of PER and CRY transcription, thereby maintaining the stable operation of the circadian clock (14–16). At the level of species evolution, the PER gene family has generated multiple paralogous genes (e.g., PER1/PER2/PER3) in vertebrates through gene duplication events. Among them, PER1 plays a critical role in maintaining rhythm plasticity, and its cis-regulatory elements exhibit characteristics of rapid evolution across different lineages (17, 18).

2.2
Rhythmicity and tissue-specificity of PER1 expression
The expression of PER1 exhibits variations across individuals of different ages and genders, with distinct temporal fluctuations throughout a 24-hour period (19). Accumulating evidence indicates that PER1 expression follows a well-defined circadian pattern. For example, in human peripheral blood, PER1 expression displays a diurnal phase, peaking at 9:00 AM and remaining low during nighttime (11), Similarly, PER1 messenger RNA (mRNA) levels are downregulated between Zeitgeber time (ZT) 0–2 and reach maximal expression between ZT 12–14 (20).
The expression of PER1 is not confined to SCN, the primary circadian pacemaker, but is widely distributed across peripheral tissues and cells. Its expression levels and functional roles are tissue-specific, contributing to the specific regulation of local tissues. For instance, within the SCN, PER1 can respond to light stimuli and participate in the regulation of circadian rhythms. In peripheral tissues such as the liver and kidneys, PER1 controls physiological rhythms by regulating gene expression, thereby influencing metabolic processes, body temperature, blood pressure, and other physiological functions. In tumors, the low expression of PER1 may be associated with the regulation of tumor cell proliferation, invasion, and apoptosis (21–23).

2.3
Regulatory mechanisms of PER1
The stability of PER1 is regulated by casein kinase 1 (CK1), which modulates its degradation rate through phosphorylation of specific domains (e.g., D1 and D2) in PER1, thereby determining the length of the circadian period. The phosphorylation status of PER1 (such as CK1-mediated phosphorylation) influences its stability and the transcription of downstream genes, which holds significant pathological implications in various diseases (24, 25). Far upstream element-binding protein 1 maintains circadian rhythm stability by regulating the rhythmic expression of PER1 protein; its depletion leads to disruptions in the oscillatory pattern of PER1 protein (26). The mRNA expression of PER1 is negatively regulated by fragile X mental retardation protein (FMRP), and the absence of FMRP results in disturbances in the oscillation of PER1 protein (27).
Studies have demonstrated that the expression of PER1 is significantly influenced by external environmental factors (such as light exposure and nutritional status) and genetic variations. For example, light can regulate PER1 expression in the SCN via the retinohypothalamic tract, while time-restricted feeding affects the oscillation of PER1 in peripheral tissues by modulating intestinal hormones and metabolic signals (28–31). PER1 is also dynamically regulated by hormones, receptors, and other metabolites. Specifically, glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) bind to the PER1 promoter in a periodic manner, dynamically regulating PER1 transcription through the formation of homodimers or heterodimers (32); acute stimulation with glucocorticoids can directly induce PER1 mRNA expression (33–35); and cellular iron levels can also modulate PER1 expression (36).
In summary, PER1 protein exhibits a distinct circadian expression pattern, with its expression levels precisely regulated by phosphorylation, epigenetic modifications, external environment, hormones, and receptor signals. It exerts tissue-specific functions in both central and peripheral tissues, participating in the regulation of fundamental life processes such as cellular metabolism, proliferation, and differentiation, and thus holds significant implications in various diseases.

3
Role and mechanism of PER1 in diseases
Recent studies have revealed that abnormal expression or functional impairment of PER1 is closely associated with the occurrence and progression of various diseases. In cardiovascular diseases, PER1 regulates blood pressure and renal function, and is involved in the anti-inflammatory mechanism of vascular injury. In the nervous system, PER1 regulates ischemic brain injury, sleep homeostasis, and associates with neurodegenerative diseases. In metabolic disorders, PER1 modulates endocrine function, glucose and lipid metabolism, as well as energy balance. In immune-related diseases, it regulates immune cell functions and inflammatory signaling pathways. In tumors, PER1 exerts tumor-suppressive effects and its low expression links to poor prognosis.
3.1
Cardiovascular diseases
PER1, a core component of the circadian clock system, is increasingly recognized as a key regulator of cardiovascular physiology and pathology. Its rhythmic expression in cardiovascular tissues (e.g., heart, blood vessels, and regulatory organs like the kidneys) integrates circadian rhythms with cardiovascular function, and its dysregulation contributes to the development and progression of various cardiovascular diseases (Table 1).
3.1.1
Regulation of blood pressure, sodium metabolism, and renal function
The PER1 gene plays a critical role in regulating blood pressure, sodium metabolism, and renal function, particularly in salt-sensitive hypertension and renal injury. Studies have shown that Dahl salt-sensitive rats with PER1 gene knockout (KO) exhibit elevated blood pressure, increased renal expression of endothelin-1 (ET-1), and exacerbated renal damage (37, 38). In PER1−/− rats, plasma aldosterone levels and MR expression are elevated; specifically, KO of PER1 in distal nephrons and collecting ducts leads to increased aldosterone levels and enhanced renal Na+ retention (39). PER1 gene knockout displays significant sex-dependent differences across various animal models (e.g., mice and rats): male mice show a more pronounced response to KO of PER1, characterized by more severe hypertension and renal injury, whereas female mice remain unaffected (40).Mechanistically, PER1 influences renal sodium handling and blood pressure rhythms by regulating the expression and activity of ET-1, thereby antagonizing salt load-induced vascular contraction and fibrosis. This suggests that PER1 may be involved in the progression of hypertension by regulating the renin-angiotensin-aldosterone system (RAAS). Studies have shown that the interaction between PER1 and CK1 affects its phosphorylation and degradation, and CK1 regulates MR function by directly phosphorylating MR and indirectly phosphorylating MR co-regulators, implying a potential close regulatory relationship between PER1 and MR (24, 25, 41). Furthermore, studies have found that GPR183 disrupts circadian rhythm signaling by inhibiting PER1 expression, thereby promoting endothelial senescence and dysfunction through the cyclic 3’,5’-adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP-response element binding protein (CREB) signaling pathway (42). In addition, in hypertension models, PER1 and the orexin system genes exhibit coordinated regulation of expression, which may influence the pathogenesis of sleep apnea syndrome (43).

3.1.2
Involvement in the anti-inflammatory mechanism of vascular injury
PER1 is involved in the anti-inflammatory mechanism of vascular ischemic injury. Liposomal prednisolone can induce the translocation of glucocorticoid (GC) receptors to the nucleus and upregulate the expression of PER1 mRNA, indicating that PER1 may participate in the anti-inflammatory mechanism of liposomal prednisolone in renal ischemia-reperfusion injury in rats (44). PER1 enhances myocardial tolerance to ischemia by maintaining circadian rhythms. In myocardial ischemia-reperfusion injury, KO of PER1 and PER2 genes impairs antioxidant and anti-inflammatory capacities, thereby exacerbating myocardial damage. The underlying mechanism is that PER1/PER2 double-knockout mice, due to circadian rhythm disruption, fail to activate rhythmic genes such as sirtuin 1 (SIRT1), leading to reduced antioxidant and anti-inflammatory capabilities (45). PER1 also contributes to the SCN-mediated cardioprotective mechanism. Studies have demonstrated that disruption of SCN function can induce the polarization of macrophages toward an anti-inflammatory phenotype by upregulating insulin-like growth factor 2 (IGF2), thereby improving cardiac repair after myocardial infarction. This mechanism may involve PER1 indirectly regulating the IGF2-mediated anti-inflammatory pathway through maintaining normal SCN function or synergizing with other rhythmic genes (46). In a mouse model of hindlimb ischemia (HLI), reduced expression of PER1 in skeletal muscle is associated with abnormal macrophage polarization (increased CD68) and decreased angiogenesis (reduced CD31). Overexpression of PER1 alleviates myocyte injury and promotes blood flow recovery via mechanisms involving the inhibition of macrophage M1 polarization and proinflammatory factor release, while activating the vascular endothelial growth factor (VEGF) pathway. This finding provides a novel therapeutic target for peripheral arterial disease (47).

3.2
Neurological disorders
PER1 exerts a pivotal role in neurological disorders, including ischemic brain injury, sleep homeostasis, and degenerative neuropathies, through multiple regulatory pathways such as circadian rhythm modulation, cell autophagy, oxidative stress, cellular apoptosis, and neurotransmitter systems (Table 2).
3.2.1
Maintaining autophagic activity in ischemic brain injury
In ischemic stroke, the enlargement of cerebral infarct volume has been associated with circadian rhythm disruption. Genetic variation at the rs2253820 locus of the PER1 gene has been shown to exacerbate the circadian rhythm of blood pressure (48). In a mouse model of cerebral ischemia, KO of PER1 eliminated the circadian variation in infarct volume, abolishing the protective effect observed during the active phase (nighttime). This was accompanied by impaired degradation of the glutamate ionotropic receptor AMPA type subunit 1 (GluA1) and reduced autophagic activity. In wild-type mice, ischemia during the active phase triggered sequestosome 1 (p62) - mediated selective autophagic degradation of GluA1 receptors, a process that was disrupted in the absence of PER1. These findings suggest that PER1 mitigates excitotoxicity by maintaining circadian regulation of autophagy-dependent GluA1 degradation (49). A study showed that levels of the proapoptotic factors cytochrome c (Cyt c) and apoptotic protease activating factor 1 (Apaf1) were higher in PER1−/− mice and basal LC3 levels were dramatically reduced. It is indicated that PER1 deficiency may slow down the autophagic machinery, increasing neuronal susceptibility to cerebral ischemia (50). Consistently with this, another study reported that hippocampal neurons from PER1−/− mice exhibited resistance to rapamycin-induced autophagy activation, as indicated by unchanged autophagic markers (e.g., LC3-II/LC3-I ratio), further underscoring the indispensable role of PER1 in maintaining basal autophagic activity (51).

3.2.2
Regulation of sleep homeostasis
Whereas inverse associations were observed with sleep latency, as well as α, β, and δ wave activities in the O1-A2 electrode derivation (52, 53). Moreover, coordinated changes in the co-expression of PER1 and CRY1 suggest that the core clock gene network plays a critical role in post-stroke sleep homeostasis disruption. In a rat model of ischemic stroke, pineal PER1 mRNA and protein levels were significantly elevated, particularly in aged rats, which correlated with sleep-wake cycle disturbances, increased cortisol levels, and decreased melatonin secretion (54). In clinical populations, reduced PER1 expression has been reported in individuals with chronic insomnia or those working night shifts, potentially linking circadian dysregulation to accelerated neurodegenerative processes, although the underlying mechanisms remain to be fully elucidated (55).

3.2.3
Association of PER1 with neurodegenerative diseases
Genetic variants of PER1 have been directly linked to Parkinson’s disease (PD), particularly in the pathogenesis of motor dysfunctions (56, 57). Genetic analyses revealed significant enrichment of loss-of-function variants (e.g., missense mutations) in the PER1 gene among PD cohorts, which were associated with dyskinesia. A whole-exome sequencing study confirmed that PD patients carrying deleterious PER1 variants exhibited a higher incidence of dyskinesia, highlighting these variants as critical risk factors for PD-related motor symptoms (58). Gu et al. reported a significant association between clock genes and sporadic PD in the Chinese population, with the PER1 variant rs2253820 showing a stronger positive correlation in postural instability and gait disorder (PIGD) subtypes (59). These findings underscore PER1 as a susceptibility gene for PD.
Mechanistically, the variants of PER1 may disrupt dopamine signaling or circadian output pathways, leading to neuronal dysfunction and progressive degeneration. This is supported by animal studies demonstrating that PER1 upregulation in the nucleus accumbens is associated with dopamine D2 receptor activation, potentially modulating neurotransmitter release and influencing alcohol addiction behaviors (60, 61). Furthermore, PER1 genotypes (e.g., AG carriers of the risk allele G) have been associated with depressive states and altered white matter integrity, which may manifest as comorbid symptoms in neurodegenerative diseases such as Alzheimer’s disease (AD). Brain imaging data showed that AG carriers had a higher prevalence of depression and microstructural damage in white matter regions such as the corpus callosum compared to AA homozygotes (62). These results suggest that PER1 may contribute to the symptomatology of neurodegenerative diseases by regulating emotion-related signaling pathways (e.g., dopamine or glutamate systems).
PER1 influences AD risk through genetic polymorphisms and plays a critical role in hippocampal aging and AD pathology by regulating glial function, amyloid metabolism, and autophagic pathways. A significant association was identified between the rs3027178 polymorphism in the PER1 circadian gene and AD risk, with the G allele conferring a protective effect (63). Additionally, KO of PER1 accelerates age-related hippocampal changes in 24-month-old mice, including microglial morphological alterations, Aβ and lipofuscin deposition, and presenilin overexpression. These alterations are attributed to impaired autophagy and excessive accumulation of misfolded proteins in the hippocampus, thereby increasing neuronal vulnerability (64, 65).
In degenerative diseases, changes in PER1 expression are not only associated with specific disorders but also broadly involved in regulating behavior, memory, and neural functions. PER1 modulates time-dependent memory formation by gating the phosphorylation of CREB in the hippocampus (activated exclusively during the daytime), thereby linking circadian rhythms to learning efficiency (66, 67). Studies have shown that synaptotagmin 14 (SYT14) gene deficiency leads to a significant upregulation of PER1 expression in the hippocampus, accompanied by behavioral alterations (e.g., hyperactivity), which are related to dysregulated neural signaling pathways. PER1 may exacerbate neural damage by affecting ion transport and apoptotic signaling; ultrastructural studies further confirmed abnormal vesicle counts, suggesting an impact of PER1 on synaptic function (68). This mechanism is particularly crucial in degenerative diseases, as neurodegenerative disorders often involve protein homeostasis imbalance and mitochondrial dysfunction (69).

3.3
Endocrine and metabolic diseases
PER1 functions as a critical integrator of circadian rhythms and metabolic/endocrine signals, regulating glucose and lipid homeostasis, maintenance of energy balance, reproductive endocrine balance, and trace element metabolism (Table 3).
3.3.1
Regulation of lipid metabolism
The PER1 gene can influence fat accumulation by regulating adipocyte differentiation and metabolism. Overexpression of PER1 upregulates the expression of peroxisome proliferator-activated receptor - gamma (PPAR-γ) and its target genes, while PER1 deletion protects mice from ethanol-induced liver injury by reducing hepatic lipid accumulation (70). PER1 promotes the expression of adipogenic genes (including sterol regulatory element-binding protein 1c), thereby enhancing lipid synthesis (71). Similarly, studies by GE et al. revealed that PER1 directly interacts with key hepatic enzymes involved in bile acid synthesis, such as cholesterol 7α-hydroxylase and sterol 12α-hydroxylase. The rhythmic biosynthesis of bile acids is associated with the activity and instability of bile acid synthases via the PER1/PKA-mediated phosphorylation pathway. Both fasting and high-fat stress can enhance PER1 expression, thereby increasing fat absorption and accumulation (72). Research has also found that serum triglyceride concentrations are positively correlated with CLOCK mRNA levels but negatively correlated with CRY2 and PER1 mRNA levels (73). These studies indicate that PER1 acts as an energy regulator, controlling daily fat absorption and accumulation.

3.3.2
Regulation of glucose metabolism
PER1 can affect glucose homeostasis by regulating insulin secretion and glucose uptake. It modulates the transcription of the sodium-glucose cotransporter 1 (SGLT1)—a glucose transporter—by regulating the activity of E-box elements in the SGLT1 promoter, thereby influencing glucose absorption (74). YAMAOKA et al. demonstrated that cold exposure in adipose tissue inhibits PER1 expression, and downregulation of PER1 may induce insulin resistance by impairing insulin signaling pathways (75). Xu et al. found that deletion of PER1 and PER2 exacerbates diet-induced insulin resistance and glucose intolerance, accompanied by aggravated hepatic inflammatory responses and metabolic dysregulation (76). FIGUEROA et al. reported that taurine improves obesity and diabetes by restoring the rhythmic expression of PER1 in pancreatic β-cells, suggesting that PER1 may serve as a potential target for taurine-based therapies in obesity and diabetes (77). Increased nuclear expression of PER1 can disrupt hepatic circadian clocks, further exacerbating glucose homeostasis imbalance (78). While PER1 influences blood glucose levels, blood glucose itself can regulate PER1 expression in tissues: hyperglycemia can disrupt the rhythmic expression of PER1 in the liver and olfactory bulb, leading to behavioral abnormalities (79), whereas glucose restriction induces the expression of the circadian clock gene PER1 via the AMP-activated protein kinase (AMPK) - SIRT1 pathway (80).

3.3.3
Maintenance of energy balance
The PER1 gene is also involved in regulating the body’s energy balance. Through interactions with the circadian clock system, it influences multiple aspects such as basal metabolic rate, food intake, and energy expenditure. Studies have shown that phosphorylation of PER1 determines feeding rhythms in mice, and S714 in hPER1 is a key site driving the rhythm of food intake behavior, playing a critical role in the physiological optimization of feeding behavior and energy consumption (81). Additionally, research indicates that time-restricted feeding may improve metabolic function in obese adult mice by reducing the circadian clock genes PER1 and PER2 in the liver. The underlying mechanism may involve the selective induction of hepatic PER1 during fasting; mice lacking hepatic PER1 fail to initiate autophagic flux, ketogenesis, and lipid accumulation. This suggests that the induction of PER1 may be an important mechanism by which hepatocytes integrate internal circadian rhythms and external nutritional signals to promote the appropriate utilization of calories (28, 82, 83).

3.3.4
Regulation of endocrine and copper metabolism
A study suggested that PER1 promotes ferroptosis and dysfunctional lipid metabolism in granulosa cells in polycystic ovary syndrome (PCOS) by inhibiting sterol regulatory element-binding factor 2 (SREBF2)/arachidonate 15-lipoxygenase (ALOX15) signaling pathway (84). However, another study revealed that decreased PER1 and PER2 promoted androgen excess via insulin-like growth factor-binding protein 4 (IGFBP4) and sex hormone binding globulin (SHBG) in the liver (85).
In addition, overexpression of PER1 can reduce intracellular copper accumulation and alleviate nephrotoxicity by upregulating the copper chaperone protein antioxidant 1 copper chaperone (Atox1) (86). However, one study has found that the overexpression of PER1 may exacerbate Cu-induced hepatotoxicity by downregulating Cu transporter Atp7b in Hepa1–6 cells (87). We hypothesize that PER1 may exert distinct regulatory effects on copper metabolism across different tissues.

3.4
Immune and inflammatory-related diseases
PER1 regulates immune cell functions, inflammatory factor expression, and signaling pathways, thereby playing a critical role in immune and inflammatory responses (Table 4), with significant implications particularly in the pathogenesis of inflammatory bowel disease and allergic airway inflammation.
3.4.1
Regulation of immune cell functions
In T cells, the stress signaling pathways mediated by adrenergic and glucocorticoid hormones inhibit mTORC1 in naive CD4+ T cells by regulating the expression of the circadian rhythm gene PER1, thereby suppressing Th1 polarization (88). Double KO of PER1 and PER2 induces ferroptosis in splenic lymphocytes, leading to a reduction in the number of splenic immune cells, structural damage, and impairment of immune function (89). Circadian clock disturbances impair the stability and function of Treg cells through PER1-related cytochrome c oxidase subunit 7C (COX7C) - dependent mitochondrial metabolic processes, exacerbating diseases such as autoimmune uveitis (90), indicating that PER1 is a key factor in maintaining the stability and function of regulatory T (Treg) cells. PER1 plays an important regulatory role in the rhythm of natural killer (NK) cells and can mediate the circadian expression of interferon-gamma (IFN-γ), perforin, and granzyme B (91). Many studies have demonstrated a close association between PER1 and macrophages. Mutations in PER1 and PER2 disrupt circadian rhythms and boost macrophage inflammation (71). PER1 interacts with PPAR-γ to curb hepatic macrophage recruitment (92), shifts macrophage polarization from M1 to M2 (41), and reins in macrophage inflammatory signaling to spur cell reprogramming (93). In addition to the above immune cells, B cells are also regulated by clock elements. Dynamic regulation of PER1Venus levels has been observed during B cell development, with a sharp increase in reporter gene expression during the transitional phase (94).

3.4.2
Regulation of inflammatory signaling pathways
PER1 can also participate in autoimmune pathological processes by regulating inflammatory signaling pathways. Studies have found that inflammatory cytokines such as tumor necrosis factor - alpha (TNF-α), interleukin (IL) - 1β, IL-6, and chemokine (C-C motif) ligand 2 (CCL2) are increased in the serum and liver of PER1-/- mice. The underlying mechanism may be that PER1 interacts with PPAR-γ in the promoter region of the CC chemokine receptor 2 (Ccr2) gene, thereby enhancing PPAR-γ-mediated transcriptional inhibition of Ccr2 and attenuating excessive innate immune responses in endotoxin-induced liver injury (92). PER1 can regulate IL-1β-induced matrix metalloproteinase (MMP) 13 expression in mandibular condylar chondrocytes through the nuclear factor-kappa B (NF-κB) pathway (95). And PER1 can regulate the production of CCL2 and IL-6 through the activation of p38 mitogen-activated protein kinase (p38), c-Jun N-terminal kinase 1 (JNK1), and NF-κB in spinal astrocytes (96).

3.4.3
Participate in the pathogenesis of inflammatory diseases
Circadian clock genes (including PER1) are downregulated in intestinal tissues and peripheral blood mononuclear cells of patients with inflammatory bowel disease (IBD) (97). PER1 plays a critical role in maintaining intestinal barrier function. Studies have shown that intestinal mucosal barrier function is weakened in PER1/PER2 double-KO mice, accompanied by exacerbation of chronic colitis. Colon biopsy results reveal significantly upregulated wee1-like protein kinase (WEE1) mRNA levels and enhanced expression of cellular inhibitor of apoptosis protein 2 (cIAP2). The potential mechanism suggests that double-KO of PER1/PER2 triggers impaired cell division during proliferation via Wee1, leading to upregulation of anti-apoptotic pathways (98). In an ovalbumin-induced allergic airway inflammation model, PER1 protein expression is significantly upregulated in mouse lung tissues. PER1 may serve as a negative regulator of melatonin against Th2-type airway inflammation (99). Additionally, research has identified a functional PER1-like domain-containing protein 1 (PERLD1). PERLD1 haplotype can alter the sensitivity of peripheral blood mononuclear cells (PBMCs) through influencing soluble glycosylphosphatidylinositol anchor protein (sGPI-AP) levels, potentially contributing to individual susceptibility to allergic asthma (100).

3.5
Tumor
3.5.1
Low expression of PER1 and its prognostic relevance
PER1 is significantly downregulated in various malignant tumor tissues, including breast cancer, lung cancer, prostate cancer, and oral squamous cell carcinoma (101–103). The downregulation of PER1 is associated with poor prognosis: patients with high PER1 expression in gastric cancer exhibit prolonged survival (P = 0.0028) (104). In breast cancer tissues, high PER1 expression is correlated with longer overall survival and recurrence-free survival (HR: 0.78, 95% CI: 0.63–0.97) (105). In ovarian cancer, low PER1 expression is linked to reduced overall survival, particularly in early-stage (I+II) patients where low expression indicates poor prognosis (106).

3.5.2
Core mechanisms of PER1 in tumor suppression
PER1 plays an important role in various tumors, such as cholangiocarcinoma, glioma, oral squamous cell carcinoma, nasopharyngeal carcinoma, prostate cancer, and gastric cancer (Table 5). Its mechanisms involve cell proliferation, apoptosis, cell cycle progression, metabolism, immune regulation, etc.
3.5.2.1
Regulation of cell proliferation, apoptosis and cell cycle progression
Abnormal expression of PER1 disrupts cell cycle progression, inhibits DNA damage repair, and affects tumor development by regulating cell proliferation and apoptosis. Studies have shown that PER1 overexpression sensitizes human cancer cells to DNA damage-induced apoptosis, whereas PER1 inhibition attenuates apoptosis in similarly treated cells (107, 108). Abnormal PER1 expression leads to dysregulation of multiple genes associated with cell cycle arrest and apoptosis, including Cyclin (CCN) B1, D, E, WEE1, cyclin-dependent kinase (CDK) 1, c-myc, tumor protein p53 (p53), and cyclin-dependent kinase inhibitor 1A (p21) (109–111). As a key regulator of DNA damage repair and cell cycle, p53 mediates PER1-dependent transcriptional regulation of WEE1 and CCNB1 (112, 113). In cholangiocarcinoma, PER1 overexpression suppresses cell proliferation by upregulating cell cycle regulators (e.g., WEE1, CREB phosphatase 1, CRE-BP1), increasing the proportion of G2/M and S phase cells, and reducing G1 phase cell populations (114). In glioma, PER1 may enhanced checkpoint kinase 2 (CHK2) - p53 signaling and proapoptotic processes and downregulation of PER1 decreases radiosensitivity and apoptosis in X-ray-irradiated U343 glioma cells (111). PER1 also regulates G1/S transition by modulating p21-mediated inhibition of CDK2/4/6 (113, 115), and sensitizes cancer cells to ionizing radiation-induced apoptosis via c-Myc-dependent suppression of p21-mediated cell cycle arrest (109). In oral squamous cell carcinoma, KO of PER1 promotes cell growth, proliferation, apoptosis resistance, migration and invasion, accompanied by upregulated mRNA expression of Ki-67, mouse double minute 2 homolog (MDM2), B-cell lymphoma 2 (BCL-2), MMP2, MMP9, and downregulated expression of cellular MYC proto-oncogene (C-MYC), p53, BCL-2 associated X protein (BAX), tissue inhibitor of metalloproteinases 2 (TIMP-2) (116). Additionally, PER1 overexpression reduces invasion and migration of nasopharyngeal carcinoma cells (117).

3.5.2.2
Suppression of metabolic reprogramming
In prostate cancer, PER1 interacts with the androgen receptor (AR), serving as a negative regulator of AR activity. Activated AR stimulates PER1 expression, which in turn attenuates AR signaling to maintain hormonal homeostasis (101). The methylation status of the PER1 promoter is negatively correlated with estrogen receptor (ER)-positive expression in breast cancer, suggesting that PER1 methylation variations may influence ER expression (118). In oral squamous cell carcinoma (OSCC), PER1 inhibits glycolysis-mediated cell proliferation by forming a PER1/receptor for activated C kinase 1 (RACK1)/phosphatidylinositol 3-kinase (PI3K) complex, regulating PI3K stability, and modulating PI3K/protein kinase B (AKT) signaling-dependent mechanisms (103, 119). In trastuzumab-resistant gastric cancer cells, PER1 complexes with PPAR-γ to promote upregulation of hexokinase 2 (HK2), thereby enhancing glycolytic activity (120).

3.5.2.3
Modulation of immune microenvironment
PER1 expression levels are associated with tumor immune infiltration, participating in immune evasion by influencing immune factor expression and immune cell recruitment. Studies have shown that PER1 expression in ovarian cancer is positively correlated with infiltration of neutrophils, Treg cells, and M2-type macrophages (106). Additionally, PER1 overexpression in endometrial cancer cells promotes the expression of immune factors TNF-α and IL-6, while upregulating immune checkpoints programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1). This may inhibit tumor invasion by activating immune responses (121).

4
Conclusions and prospects
As a core gene of the circadian clock, PER1 plays a critical role in the occurrence and development of various diseases through complex mechanisms and signaling pathways (Table 6). Its abnormal expression and functional disorders widely affect the physiological and pathological processes of the organism. Based on existing studies, the function of PER1 exhibits tissue specificity, but its mechanisms of action in different organs/diseases remain incompletely understood. Moreover, most current research is based on animal or cell models, but there are not many clinical studies on PER1 and large-scale clinical validation remains lacking (Table 7), especially in the development of gene therapy or targeted drugs. In-depth studies on the mechanisms of PER1 in different diseases provide new perspectives for understanding the pathogenesis of these diseases and lay a theoretical foundation for the development of therapeutic strategies based on circadian rhythm regulation.
Future research on PER1 is expected to achieve breakthroughs in the following aspects: First, to further clarify the specific regulatory mechanisms of PER1 in different tissues and cell types, particularly its dynamic changes during disease occurrence and progression. Second, to develop drugs or therapeutic approaches that can precisely target PER1 and its related signaling pathways, such as the development of drugs based on CK1 inhibitors or FMRP mimetics, to restore the normal function and rhythm of PER1. Third, to explore PER1 as a biomarker for disease diagnosis and prognosis assessment, enabling early disease diagnosis and personalized treatment by detecting PER1 expression levels, rhythm changes, etc. With the continuous in-depth study of PER1, it is believed that disease prevention and treatment strategies based on circadian rhythm regulation will bring new hope for improving human health.