PIK3CG deficiency promotes metabolic reprogramming in pancreatic Cancer by suppressing GLS2-driven glutamine metabolism

Background Pancreatic ductal adenocarcinoma (PDAC) undergoes profound metabolic reprogramming. This study aims to elucidate how PIK3CG deficiency drives glutamine (Gln) metabolic reprogramming in PDAC. Methods We first identified PIK3CG as a key differentially expressed gene in PDAC and confirmed that its expression level correlates with patient survival. We established both in vitro and in vivo PIK3CG -knockdown ( PIK3CG -KD) models. Using these models, we assessed its regulatory effects on the Gln metabolic pathway, mitochondrial reactive oxygen species (mtROS) accumulation, mitochondrial membrane potential, and tumor cell pyroptosis. Moreover, we delineated the specific molecular mechanism linking PIK3CG to downstream signaling. This mechanism crucially involves GLS2 , a key enzyme in glutamine metabolism. Results PIK3CG deficiency suppresses the mechanistic target of rapamycin complex 1 (mTORC1) pathway, leading to enhanced phosphorylation of S6K2. This disrupts the interaction between nuclear S6K2 (Glu163) and P53 (Arg273), ultimately inhibiting GLS2 transcription. Consequently, a series of metabolic disturbances ensue: glutamate (Glu) accumulates substantially, Gln catabolism is blocked, and its influx into the TCA cycle is restricted, resulting in reduced α-ketoglutarate (α-KG) levels. The deficiency in α-KG triggers a significant accumulation of mtROS. Notably, despite elevated ROS levels, pyroptosis is suppressed and accompanied by exacerbated inflammation. Conversely, GLS2 overexpression rescues all the aforementioned phenotypes induced by PIK3CG -KD—including tumor growth, elevated mtROS, suppression of pyroptosis, and inflammatory response—while restoring Gln metabolic homeostasis. Conclusion Our study reveals a novel mechanism by which PIK3CG -KD regulates Gln metabolism and mitochondrial function via the S6K2/P53/GLS2 axis, providing a rationale for metabolic intervention and precision therapy in PIK3CG -deficient PDAC.