Authors
Zhe Zhang, Ningna Weng, Xuanhao Gu, Yi Zang, Qitai Chen, Rujia Zheng, Xishan Yang, Gubu Amu, Danyang Zhao, Zhihao Ma, Jinyan Huang, Tingbo Liang, Qi Zhang
Published in
EMBO molecular medicine. Aug 13, 2026. Epub Aug 13, 2026.
Abstract
Pancreatic cancer (PC) continues to demand urgent therapeutic innovation given its limited treatment options. Here, through phenotypic screening of a natural product library followed by systematic validation, we identified chrysosplenetin (CHR) as a bioactive compound with anti-PC activity. Transcriptomic profiling and functional analyses demonstrated that CHR induced endoplasmic reticulum (ER) stress, thereby activating the unfolded protein response (UPR) and subsequent apoptosis, while paradoxically triggering a protective autophagy. Genetic or pharmacological inhibition of autophagy potentiated CHR-induced antitumor efficacy. Using an integrated approach including proteomic analysis, bio-layer interferometry, cellular thermal shift assay, and molecular docking, we confirmed TMED3 as a direct target of CHR. Functional studies revealed that disruption of TMED3 expression partially restored ER homeostasis, attenuating CHR-induced UPR activation and apoptosis. Furthermore, CHR combined with standard chemotherapy or autophagy inhibitors exhibited enhanced antitumor activity in preclinical models, providing a basis for future therapeutic exploration of the TMED3-ER stress axis. Together, our findings establish TMED3 as a novel therapeutic target in PC, revealing that disrupting ER proteostasis via TMED3 perturbation represents a potential therapeutic strategy warranting further investigation.
PMID:
42595827
Bibliographic data and abstract were imported from PubMed on 14 Aug 2026.
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