SIRT7 Mediated‐PTEN Desuccinylation Drives Gastric Tumorigenesis by Activating PI3K/AKT Pathway

SIRT7 is linked to cancer, yet its function in gastric cancer (GC) remains unclear. PTEN suppresses the PI3K/AKT pathway in GC, its regulation via lysine succinylation and interplay with SIRT7 is unknown. SIRT7 expression was analyzed using TCGA, Human Protein Atlas, clinical samples, and GC cell lines via qRT‐PCR, immunoblotting, and immunohistochemistry. SIRT7 was silenced using shRNA, and functional effects were assessed through proliferation, migration, invasion, and xenograft assays. SIRT7‐PTEN interaction was validated by co‐immunoprecipitation and confocal microscopy, while PTEN stability was examined using cycloheximide chase and mutagenesis. We observed elevated SIRT7 expression in GC, correlating with reduced survival. SIRT7 inhibition markedly impaired tumor growth and metastasis. SIRT7 binds PTEN and desuccinylates it at K322/K330, promoting ubiquitin‐mediated degradation. This destabilization of PTEN leads to the activation of the PI3K/AKT signaling pathway. Rescue experiments confirmed that PTEN depletion reverses the tumor‐suppressive effects of SIRT7 silencing. Thus, SIRT7 drives gastric carcinogenesis by destabilizing PTEN through site‐specific desuccinylation and subsequent activation of the PI3K/AKT axis. This reveals succinylation as a stabilizing modification for PTEN and identifies the SIRT7‐PTEN axis as a potential therapeutic target to restore tumor suppression in GC.