FTSJ3‐Mediated 2′‐O‐Methylation of HSPA5 mRNA Stabilizes BOP1 via SUMOylation to Drive DRP1‐Dependent Mitochondrial Fission and Fatty Acid Oxidation in Lung Squamous Cell Carcinoma

Lung squamous cell carcinoma (LUSC) is a highly aggressive malignancy with a dismal prognosis and limited targeted therapies. While post-translational and RNA modifications are implicated in tumor progression, their precise roles in LUSC remain elusive. Here, we identify the RNA methyltransferase FTSJ3 as a critical oncogenic driver. FTSJ3 is markedly upregulated in LUSC tissues, and its high expression correlates with poor patient survival. Mechanistically, FTSJ3 catalyzes 2'-O-methylation of HSPA5 mRNA, leading to transcript stabilization and increased protein abundance of the molecular chaperone HSPA5. Elevated HSPA5 facilitates the SUMOylation and subsequent stabilization of the ribosomal biogenesis factor BOP1. This modification event activates the DRP1/SREBP1 signaling axis, driving excessive mitochondrial fission and reprogramming cellular metabolism towards fatty acid oxidation (FAO), providing essential energy and biomolecular precursors for tumor growth. Silencing of FTSJ3 disrupts this HSPA5/BOP1/DRP1 cascade, inhibiting mitochondrial fragmentation, FAO, and the proliferation, migration, and invasion of LUSC cells. In vivo, delivery of FTSJ3-specific siRNA via liposomal nanoparticles suppresses tumor growth and metastasis in LUSC models. Our findings delineate a novel FTSJ3-HSPA5-BOP1-DRP1-SREBP1 axis that integrates RNA methylation with SUMOylation, mitochondrial dynamics and lipid metabolism to promote LUSC progression, nominating FTSJ3 as a therapeutic target for this cancer.