Abstract
Gastric cancer remains a major global health burden. Its high incidence and mortality highlight the urgent need to elucidate its underlying pathogenic mechanisms and develop more effective therapeutic strategies. In recent years, metabolic reprogramming has emerged as a cancer hallmark, with dysregulated sphingolipid metabolism increasingly recognized as a critical driver of tumor progression and immune evasion. Although substantial evidence links sphingolipid metabolism to gastric carcinogenesis, the underlying regulatory mechanisms remain poorly understood. Serine palmitoyltransferase small subunit A (SPTSSA) is a key regulatory component of the serine palmitoyltransferase complex, the rate-limiting enzyme responsible for the first step of de novo sphingolipid biosynthesis and the maintenance of cellular sphingolipid homeostasis. Recent studies have implicated SPTSSA in gastric cancer development and progression. This review summarizes SPTSSA’s biological functions and regulatory role in sphingolipid metabolism, examines its contribution to malignant progression and remodeling of the tumor immune microenvironment in gastric cancer, and discusses the potential mechanisms underlying its aberrant expression and its possible synergistic interactions with other oncogenic pathways, including the Hippo–TEA domain transcription factor 1 (TEAD1) axis. It also evaluates SPTSSA’s translational potential as a prognostic biomarker, candidate liquid-biopsy marker, and therapeutic target for combined immunometabolic interventions. By integrating current evidence, this review aims to provide a comprehensive framework for future mechanistic and translational research on SPTSSA in gastric cancer.