{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:44:43Z","timestamp":1785415483488,"version":"3.56.0"},"reference-count":68,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:00:00Z","timestamp":1778716800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82174155"],"award-info":[{"award-number":["82174155"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"award":["82174155"],"award-info":[{"award-number":["82174155"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by therapeutic resistance and poor prognosis, underscoring the need for new therapeutic strategies. Bufalin, a major bioactive constituent of Venenum bufonis, has shown antitumor activity in several cancer types; however, its mechanism of action in PDAC remains incompletely defined. In this study, we investigated the antitumor effects of bufalin in PDAC using in vitro assays, mouse tumor models, and integrative transcriptomic, proteomic, metabolomic, and bioinformatic analyses. Bufalin inhibited PDAC cell viability, clonogenic growth, migration, and tumor progression in vivo. Pharmacological rescue experiments indicated that ferroptosis contributes importantly to bufalin-induced cytotoxicity, although apoptosis- and pyroptosis-related pathways may also be involved. Multi-omics analyses revealed coordinated alterations in calcium homeostasis, endoplasmic reticulum (ER) stress\/unfolded protein response (UPR) signaling, and ferroptosis-related metabolic pathways. Further experiments showed that bufalin was associated with disrupted intracellular Ca2+ homeostasis, IP3R-linked ER Ca2+ release, activation of PERK\/eIF2\u03b1\/ATF4 signaling, increased ATF3 expression, reduced SLC7A11 and GPX4 expression, glutathione depletion, and enhanced lipid peroxidation. Molecular docking and surface plasmon resonance assays supported an in vitro physical interaction between bufalin and IP3R1\/IP3R3, while inhibition of ER stress attenuated several bufalin-induced ferroptosis-related phenotypes. Bioinformatic analyses further showed that higher ER stress and ferroptosis signature scores were associated with improved overall survival in PDAC, and concurrent activation of both signatures was linked to the most favorable prognosis. Collectively, these findings support that bufalin suppresses PDAC progression through coordinated ER stress- and ferroptosis-related responses, highlighting ER stress-ferroptosis crosstalk as a potential therapeutic vulnerability in PDAC.<\/jats:p>","DOI":"10.3390\/ijms27104373","type":"journal-article","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T16:27:56Z","timestamp":1778776076000},"page":"4373","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Bufalin Suppresses Pancreatic Ductal Adenocarcinoma Through ER Stress-Ferroptosis Crosstalk Associated with IP3R-Linked Ca2+ Dysregulation and ATF3\/SLC7A11 Regulation"],"prefix":"10.3390","volume":"27","author":[{"given":"Pei-Wen","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Integrative Oncology, Shanghai Cancer Center, Fudan University, Shanghai 200032, China"},{"name":"Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Integrative Oncology, Shanghai Cancer Center, Fudan University, Shanghai 200032, China"},{"name":"Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wai-Mei","family":"Si","sequence":"additional","affiliation":[{"name":"Department of Integrative Oncology, Shanghai Cancer Center, Fudan University, Shanghai 200032, China"},{"name":"Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Integrative Oncology, Shanghai Cancer Center, Fudan University, Shanghai 200032, China"},{"name":"Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang-Yu","family":"Kong","sequence":"additional","affiliation":[{"name":"Department of Integrative Oncology, Shanghai Cancer Center, Fudan University, Shanghai 200032, China"},{"name":"Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-Yi","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Integrative Oncology, Shanghai Cancer Center, Fudan University, Shanghai 200032, China"},{"name":"Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Yan","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Integrative Oncology, Shanghai Cancer Center, Fudan University, Shanghai 200032, China"},{"name":"Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Integrative Oncology, Shanghai Cancer Center, Fudan University, Shanghai 200032, China"},{"name":"Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,14]]},"reference":[{"key":"ref_1","first-page":"e70043","article-title":"Cancer statistics, 2026","volume":"76","author":"Siegel","year":"2026","journal-title":"CA Cancer J. 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