Histone methyltransferase EZH2 drives podocyte injury and senescence in diabetic nephropathy through STAT3 activation.

BACKGROUND: As a common secondary nephropathy, diabetic nephropathy (DN) is closely related to podocyte senescence. Histone methyltransferase enhancer of zeste homolog 2 (EZH2) participates in the regulation of cellular proliferation, apoptosis, and senescence. Recently, the non-histone role of EZH2 has attracted much attention. It was reported that EZH2 can directly combine with signal transducer and activator of transcription 3 (STAT3) thereby enhancing its activity. However, the association between EZH2 and STAT3 in podocyte senescence remains unclear. METHODS: To clarify the association between EZH2 and STAT3 and their functions in podocyte injury and senescence in DN, we established db/db mice and cultured mouse podocyte cells (MPCs) exposed to high glucose (HG) as DN models. EZH2 was regulated genetically and pharmacologically in this study and changes in indicators related to podocyte injury and aging were detected. KEY FINDINGS: Elevated levels of EZH2, inflammatory markers, and reduced podocyte marker proteins were observed in db/db mice and HG-cultured MPCs. Additionally, aggravated podocyte senescence was observed in the DN group. Pharmacological inhibition of EZH2 by GSK126 alleviated kidney aging and podocyte injury markers by approximately 54% in db/db mice. Moreover, we confirmed that EZH2 can bind to STAT3 and increase the methylation of its lysine residues, thereby promoting its activity. However, rescue experiments in vivo and in vitro revealed that the beneficial effect of EZH2 downregulation was counteracted by overexpression of STAT3. CONCLUSION: Mechanistically, EZH2 interacted with STAT3 and enhanced its activation, in association with increased lysine methylation of STAT3. Together, our findings identify EZH2-STAT3 signaling as a key driver of podocyte injury and senescence in DN and suggest that targeting EZH2 may represent a promising therapeutic strategy for DN. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-026-06136-x.