KAT2A alleviates the glucose starvation-induced mitochondrial oxidative stress and ferroptosis to promote colon cancer progression.

Beyond its established role as a lysine acetyltransferase, KAT2A has recently been identified to possess succinyltransferase activity. This study aims to investigate the function of KAT2A in mediating succinylation modification of heat shock protein 60 (HSP60) and to elucidate the underlying mechanism through which KAT2A regulates mitochondrial oxidative stress and ferroptosis induced by glucose starvation in colon cancer cells via HSP60 succinylation. Bioinformatic analyses were conducted to assess KAT2A expression in colon cancer and its association with patient prognosis. Protein interaction between KAT2A and HSP60 was examined by co-immunoprecipitation (Co-IP). Intracellular Fe²⁺ levels, lipid peroxidation, and mitochondrial reactive oxygen species (mtROS) were measured using FerroOrange, C11 BODIPY 581/591, and MitoSOX Red fluorescent probes, respectively. Mitochondrial localization and membrane potential were evaluated via immunofluorescence assays. KAT2A is upregulated in colon cancer and correlates with poor prognosis, largely attributable to its ability to enhance cell viability and invasion under glucose deprivation. Overexpression of KAT2A conferred resistance to glucose starvation-induced ferroptosis by mediating HSP60 succinylation. Label-free quantitative proteomic analysis identified three critical succinylation sites on HSP60 (K72, K133, K191), with K191 being the principal site regulating ferroptosis. Succinylated HSP60 interacts with GSTK1 and promotes the mitochondrial translocation of the HSP60-GSTK1 complex, mitigating mitochondrial oxidative stress under glucose starvation. Through this mechanism, KAT2A suppresses ferroptosis and supports colon cancer cell survival and tumor growth. The KAT2A-HSP60-GSTK1 axis attenuates glucose starvation-induced mitochondrial oxidative stress, thereby inhibiting ferroptosis and promoting tumor progression in colon cancer.