Treating lung squamous cell carcinoma (LUSC) remains a formidable challenge due to high relapse rates and limited targeted options, however, while inducing single modes of cell death like apoptosis often fails to eradicate tumors, the potential to simultaneously trigger multiple death pathways has remained largely unexplored.

Here, we identify Sanguinarine (SAG), a natural benzophenanthridine alkaloid, as a potent “switch” that synchronously induces both apoptosis and ferroptosis in LUSC, and we reveal that it achieves this by directly hijacking the ER chaperone protein BiP. Unlike its normal protective role, SAG binds to and up-regulates BiP, which paradoxically activates the PERK/eIF2α/CHOP/GADD34 signaling axis to induce catastrophic Endoplasmic Reticulum Stress (ERS); this “overload” simultaneously drives iron-dependent ferroptosis and caspase-mediated apoptosis, leaving the cancer cells no escape route.

This work provides a new strategy based on targeting BiP to switch ER stress from a survival mechanism to a lethal “double strike,” and highlights SAG as a potent agent capable of launching synchronous death signals against LUSC. The work entitled “Sanguinarine triggers apoptosis and ferroptosis synchronously by directly binding BiP in lung squamous cell carcinoma” was published on Chinese Journal of Natural Medicines. (published on April 20, 2026).
DOI：10.1016/S1875-5364(26)61115-6