TMEM45A Mediates Gastric Cancer Progression Through the P4HA1/Succinate/TGF-β Pathway

Background Gastric cancer (GC) generally presents with poor prognosis owing to late diagnosis. Transmembrane protein 45A (TMEM45A) is involved in the progression of various tumors, yet its function and molecular mechanism in GC remain unclear. Methods We screened candidate genes via public bioinformatics databases, validated TMEM45A expression by immunohistochemistry in 75 paired GC tissues, and conducted in vitro functional assays and rescue experiments to explore the underlying mechanism. Results TMEM45A was significantly upregulated in GC tissues. Its high expression was associated with postoperative residual tumor and poor treatment response, and acted as an independent poor prognostic factor for GC. A nomogram incorporating TMEM45A exhibited favorable accuracy in predicting GC patients’ long-term survival. Mechanistically, TMEM45A promoted GC cell proliferation, migration and invasion by physically interacting with and positively regulating P4HA1, elevating succinate levels and activating the TGF-β/Smad pathway; reintroduction of P4HA1 effectively reversed the tumor-inhibitory effects caused by TMEM45A knockdown. Conclusion TMEM45A is a novel independent prognostic biomarker for GC. It drives GC progression via the P4HA1-mediated succinate/TGF-β/Smad pathway, and may serve as a promising therapeutic target.