fig4

Figure 4. Proposed role of ADSL-associated metabolism in PDAC chemoresistance. ADSL-associated purine metabolism may support de novo purine biosynthesis and help maintain nucleotide availability in PDAC cells exposed to chemotherapeutic stress. Through purine nucleotide-pool maintenance, flux-dependent SAICAR–PKM2 signaling, and downstream effects on bioenergetic and biosynthetic programs, ADSL-associated metabolism may facilitate cellular adaptation to antimetabolite treatment. In the setting of gemcitabine exposure, ADSL-associated metabolism is proposed to attenuate replication stress and limit DNA damage, as reflected by reduced gH2AX accumulation, thereby sustaining pro-survival signaling and reducing gemcitabine cytotoxicity. ADSL: Adenylosuccinate lyase; PDAC: pancreatic ductal adenocarcinoma; SAICAR: succinylaminoimidazole carboxamide ribotide; PKM2: pyruvate kinase M2; gH2AX: gamma-H2AX; AICAR: aminoimidazole carboxamide ribotide; AMP: adenosine monophosphate.