LINC00941 Drives Chemoresistance via Modulating PKM2 Activity and Aerobic Glycolysis in Oral Squamous Cell Carcinoma.

Abstract

Cisplatin (CDDP) resistance represents a major determinant of poor prognosis in patients with oral squamous cell carcinoma (OSCC). While long non-coding RNAs (lncRNAs) are implicated in chemoresistance pathways, their mechanistic roles in OSCC treatment failure remain incompletely defined. This study identifies LINC00941 as a CDDP resistance-associated lncRNA, with elevated expression correlating significantly with adverse OSCC prognosis. Gain- and loss-of-function assays reveal that LINC00941 overexpression promotes both aerobic glycolysis and CDDP resistance in OSCC cells. Furthermore, elevated LINC00941 expression enhances pyruvate kinase activity, thereby fostering chemoresistance in vitro and in vivo. Mechanistic investigations reveal that LINC00941 physically interacts with pyruvate kinase M2 (PKM2), enhancing its protein stability by suppressing ubiquitin-mediated proteolysis. This stabilization amplifies glycolytic flux, ultimately inducing CDDP resistance in OSCC cells. Our findings elucidate a novel lncRNA-dependent pathway governing chemoresistance and propose targeting the LINC00941/PKM2/glycolysis axis as a translatable therapeutic strategy for overcoming CDDP resistance in OSCC.