{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:13:23Z","timestamp":1792790003051,"version":"4.5.0"},"reference-count":48,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"crossref","award":["23K26797"],"award-info":[{"award-number":["23K26797"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"},{"id":"https:\/\/ror.org\/00hhkn466","id-type":"ROR","asserted-by":"crossref"}]},{"award":["23K26797"],"award-info":[{"award-number":["23K26797"]}],"id":[{"id":"https:\/\/ror.org\/00hhkn466","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Pancreatic cancer cells adapt to nutrient stress by activating metabolic pathways that facilitate survival and proliferation within the tumor microenvironment, a phenomenon known as austerity. Targeting this resilience presents a strategy for developing chemotherapeutic agents with anti-austere properties. Methods: Phytochemical investigation of Nelumbo nucifera petals led to the isolation of six alkaloids: three benzylisoquinolines (1\u20133), two aporphines (4, 5), and one proaporphine (6). Preferential cytotoxicity under nutrient deprivation was evaluated. The most active compound was further analyzed in MIA PaCa-2 cells using proliferation, migration, colony formation, and three-dimensional spheroid growth assays, with additional selective cytotoxicity assessment in KLM-1 cells. Mechanistic studies examined MAPK family signaling, autophagy-associated alterations, and apoptosis. Results: (\u2212)-N-nornuciferine (5) exhibited considerable preferential cytotoxicity against MIA PaCa-2 cells (PC50 = 0.53 \u00b5M) and KLM-1 cells (PC50 = 1.11 \u00b5M). Under nutrient-rich conditions, 5 suppressed the proliferation, migration, colony formation, and spheroid growth of MIA PaCa-2 cells. Under nutrient deprivation, 5 increased MAPK phosphorylation and LC3-II accumulation while reducing p62\/SQSTM1 levels. Chloroquine (CQ) further increased LC3-II accumulation, particularly at 10 \u00b5M 5, compared with CQ alone. However, autophagy inhibitors did not rescue 5-induced loss of viability, and the pan-caspase inhibitor Z-VAD-FMK also failed to significantly mitigate cytotoxicity. No detectable PARP or caspase-3 cleavage was observed. Conclusions: (\u2212)-N-nornuciferine (5) exhibits anti-austere and anticancer activities in pancreatic ductal adenocarcinoma (PDAC) models, accompanied by MAPK phosphorylation and autophagy-related changes under nutrient deprivation conditions. Conventional caspase-dependent apoptosis is unlikely to be the main contributor to this process.<\/jats:p>","DOI":"10.3390\/ph19091454","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T09:34:01Z","timestamp":1789378441000},"page":"1454","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Aporphine Alkaloid N-Nornuciferine from Nelumbo nucifera Induces MAPK-Associated Autophagy Under Nutrient Deprivation in Human Pancreatic Cancer Cells"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-7023-9195","authenticated-orcid":false,"given":"Hung Hong","family":"Nguyen","sequence":"first","affiliation":[{"name":"Natural Drug Discovery Laboratory, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan"},{"name":"Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences, University of 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