SPTLC2 enhances radiosensitivity in esophagus cancer via promoting endoplasmic reticulum stress-induced cell apoptosis

Radioresistance remains a major barrier to effective radiotherapy in esophageal squamous cell carcinoma (ESCC). This study investigated the role of SPTLC2 in ESCC radiosensitivity. We analyzed the expression of SPTLC2 in radioresistant ESCC (ESCC RR) cells and ESCC patients after neoadjuvant chemoradiotherapy (nCRT). Pathological complete response (pCR) and overall survival (OS) were used to evaluate SPTLC2 expression on the therapeutic effects of nCRT in esophageal cancer. Clonogenic assays, flow cytometry, and xenograft models were used to assess the function of SPTLC2, while Western blot, immunofluorescence, RNA sequencing, and immunohistochemistry to uncover the underlying mechanism of SPTLC2 in ESCC radiosensitivity. Lower SPTLC2 expression was confirmed in ESCC RR and post-nCRT samples, and was significantly associated with poorer short-and long-term clinical outcomes following nCRT in esophageal cancer. Overexpressed SPTLC2 enhanced radiosensitivity and apoptosis of ESCC both in vitro and in vivo. Mechanistically, SPTLC2 localized to the endoplasmic reticulum (ER) and induced marked ER stress by increased expression of BIP, ATF4, and CHOP. Pharmacological inhibition of ER stress reversed SPTLC2-mediated radiosensitization and apoptosis. SPTLC2 overexpression positively correlated with sphingolipid metabolism, with decreased intracellular serine levels, and increased 3-ketodihydrosphingosine (3-KDS) levels. Supplementation with 3-KDS enhanced ESCC radiosensitivity, promoted apoptosis and ER stress. Catalytically inactive sphingolipid metabolism by myriocin to block endogenous 3-KDS production are necessary for SPTLC2-mediated ER-stress activation, apoptosis, and radiosensitization. Transcriptomic analysis further identified cytoskeletal organization, glycosaminoglycan biosynthesis, and amino acid metabolism was significantly enriched in SPTLC2 overexpression TE-1 cell under irradiation. Moreover, S100A9 may serve as a downstream candidate gene involved in SPTLC2 promoting ESCC radiosensitivity. SPTLC2 enhances ESCC radiosensitivity by promoting serine-dependent sphingolipid metabolic reprogramming and activating endoplasmic reticulum stress–associated apoptosis. Targeting the SPTLC2–3-KDS–ER stress axis may provide a potential strategy to improve radiotherapy efficacy in ESCC.