{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T10:36:33Z","timestamp":1787567793908,"version":"build-2736575974"},"reference-count":64,"publisher":"OAE Publishing Inc.","content-domain":{"domain":["oaepublish.com"],"crossmark-restriction":false},"short-container-title":["Cancer Drug Resist."],"abstract":"<jats:p>Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal human malignancies and is characterized by profound metabolic reprogramming and marked therapeutic resistance. Among the metabolic enzymes that sustain tumor fitness, adenylosuccinate lyase (ADSL) has emerged as a critical regulator of de novo purine biosynthesis with broader roles in oncogenic signaling, metabolic adaptation, and chemoresistance. ADSL catalyzes two key reactions in purine synthesis, contributing to adenylosuccinate-to-adenosine monophosphate (AMP) production, fumarate generation, and regulation of intermediates such as succinylaminoimidazole carboxamide ribotide (SAICAR), which functionally intersects with glycolysis and transcriptional control. In PDAC, dysregulation of ADSL-associated metabolism has been linked to aggressive tumor biology and altered therapeutic responses. Mechanistically, ADSL may modulate gemcitabine responsiveness through context-dependent effects on purine nucleotide homeostasis, replication-stress adaptation, redox regulation, and ferroptosis-associated signaling. Beyond its canonical biosynthetic function, ADSL-related metabolic flux may support adaptive survival through SAICAR\u2013pyruvate kinase M2 (PKM2) signaling, glycolytic remodeling, and fumarate-associated pathways that influence redox homeostasis, epigenetic regulation, and stress-response signaling. These interconnected mechanisms position ADSL as a context-dependent metabolic vulnerability in chemoresistant PDAC. Here, we summarize current understanding of ADSL biology and discuss its prognostic, mechanistic, and therapeutic relevance in PDAC chemoresistance, with emphasis on gemcitabine resistance, replication stress buffering, and metabolic adaptation. Targeting ADSL-associated metabolic dependencies may provide a promising strategy to disrupt the metabolic circuitry underlying PDAC aggressiveness and drug resistance.<\/jats:p>","DOI":"10.20517\/cdr.2026.58","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T09:46:03Z","timestamp":1787564763000},"update-policy":"https:\/\/doi.org\/10.20517\/oae.crossmark.policy","source":"Crossref","is-referenced-by-count":0,"title":["Adenylosuccinate lyase in pancreatic ductal adenocarcinoma chemoresistance: from purine metabolism to metabolic vulnerability"],"prefix":"10.20517","author":[{"given":"Tung-Wei","family":"Hsu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih-Ming","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yen-Hao","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Po-Hsiang","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charupong","family":"Saengboonmee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan-Yu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsin-An","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"8410","published-online":{"date-parts":[[2026,8,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.70162"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1186\/s13014-019-1345-6"},{"key":"B3","unstructured":"National Cancer Institute. 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