STIP1 drives Metabolic Reprogramming in Esophageal Squamous Cell Carcinoma via AHCY‐LDHA Axis

Glucose metabolism reprogramming has emerged as a hallmark of cancer. We have reported that high temperature food or drink (>65°C) is the key etiological factors contributing to esophageal squamous cell carcinoma (ESCC) progression. Intriguingly, we observed that heat stimulation (42°C) alters glycolytic pathways in esophagus cells, but the underlying mechanisms remain poorly understood. Our findings revealed that stress-induced phosphoprotein 1 (STIP1) exhibits elevated expression in esophageal tissues exposed to heat stimulation (>65°C) compared to unexposed tissues, and its overexpression correlated with clinical grade and predict poor prognosis in ESCC patients. Mechanistically, STIP1 interacts with and activates adenosylhomocysteinase (AHCY; also termed SAHH) and change the conformation of AHCY. STIP1 also facilitates AHCY binding to lactate dehydrogenase A (LDHA), stimulating glycolysis. Notably, AHCY recruits protein arginine methyltransferase 3 (PRMT3) to methylate LDHA at R106, inhibiting ubiquitination-mediated AHCY degradation. In vivo, STIP1 knockout in mice dramatically inhibits 4-nitrochinoline-oxide (4NQO) induced esophageal tumorigenesis. Through virtual screening and functional validation, we identified licochalcone A (LCA) as a potent inhibitor of STIP1-driven ESCC proliferation in vitro and in vivo. In summary, these findings delineate a pro-tumorigenic signaling pathway whereby heat-induced STIP1 upregulation promotes ESCC glycolysis and growth via moonlighting functions that coordinate AHCY activity and LDHA methylation.