CLDN6 inhibits breast cancer growth by inducing autophagic cell death through SOX4 m6A modification.

Breast cancer is a life-threatening malignancy with subtle early symptoms, necessitating novel biomarkers and mechanistic insights. The tight junction protein CLDN6 plays a tumor-suppressive role in breast cancer, yet its underlying molecular mechanisms remain incompletely understood. Herein, we demonstrate that CLDN6 suppresses breast cancer growth by inducing autophagic cell death through METTL14-mediated m6A modification of SOX4 mRNA. Mechanistically, CLDN6 sequesters PDLIM2 at the cell membrane, reducing nuclear PDLIM2-mediated RelA ubiquitination. Accumulated RelA transcriptionally upregulates METTL14, enhancing SOX4 mRNA m6A modification and degradation, which attenuates PI3K/Akt signaling and triggers autophagic cell death. Moreover, protein expression analysis in breast cancer tissues and bioinformatics analyses reveal an association between the CLDN6/METTL14/SOX4 axis and patient prognosis. These findings identify the CLDN6/METTL14/SOX4 axis as a promising prognostic signature and potential therapeutic target for breast cancer, highlighting the interplay among tight junction protein, epigenetic modification, and autophagic cell death as a conceptual basis for multi-targeted therapeutic strategies.