Mechanistic Study of GSDME and CXCL10 in SUV39H1-Mediated Pyroptosis and Immune Suppression in Cervical Cancer.

Cervical cancer (CC) remains a major global health challenge characterized by high incidence and mortality. The histone methyltransferase suppressor of variegation 3-9 homolog 1 (SUV39H1) has emerged as a key epigenetic regulator in tumor progression, but its role in modulating pyroptosis and remodeling of the immune microenvironment in CC remains unclear. In this study, we demonstrate that SUV39H1 promotes CC progression through dual epigenetic regulation, specifically repression of gasdermin E (GSDME) and activation of chemokine (C-X-C motif) ligand 10 (CXCL10). Overexpression of SUV39H1 in HeLa and SiHa cells enhanced histone 3 lysine 9 tri methylation (H3K9me3) deposition at the DFNA5 (GSDME) promoter, resulting in reduced transcription and suppressed GSDME-dependent pyroptosis-like cell death. Interestingly, it also upregulated CXCL10 expression. Functional assays confirmed that SUV39H1 attenuated GSDME-mediated pyroptosis-like cell death and enhanced cell migration via induction of epithelial-mesenchymal transition (EMT). Moreover, SUV39H1 drives CXCL10 secretion, which activates the chemokine (C-X-C motif) receptor 3 (CXCR3) signaling axis in macrophages and upregulates immunosuppressive molecules including programmed death ligand 1 (PD-L1), T cell immunoglobulin and mucin-domain containing-3 (Tim-3), and secreted phosphoprotein 1 (SPP1), thereby fostering an immunosuppressive tumor microenvironment (TME), and these effects appear parallel to GSDME suppression. Collectively, these findings reveal a multifaceted oncogenic role of SUV39H1 in CC, highlighting its potential as a therapeutic target for epigenetic and immunomodulatory intervention.