A natural small molecule Hdj-15 coordinates the ER and lysosomes to induce ferroptosis by targeting TrxR1.

Abstract

Ferroptosis, a type of regulated cell death characterized by lipid peroxide accumulation, has emerged as a promising subroutine of cell death capable of sensitizing chemoresistant cancer cells. To identify novel ferroptosis inducers, a natural product library of 1023 compounds was screened, leading to the identification of Hdj-15. Hdj-15 elicited oxidative stress, the unfolded protein response (UPR), lysosomal biogenesis, and massive lipid peroxidation to trigger ferroptosis. Mechanistically, Hdj-15 directly targeted TrxR1, leading to oxidative stress and ER stress. Knockdown of TXNRD1 (which encodes TrxR1) further sensitized cells to Hdj-15, and reconstitution with wild-type, but not U498C mutant, TXNRD1 reversed this effect. The IRE1α branch of the UPR was activated upon Hdj-15 treatment, which in turn enabled X-box binding protein 1 (XBP1) to directly transactivate transcription factor E3 (TFE3) and transcription factor EB (TFEB), thereby triggering lysosomal biogenesis. Chromatin immunoprecipitation (ChIP) revealed that XBP1s directly occupied the -735 to -631 and the -493 to -365 sites of the TFE3 and TFEB promoters. Hdj-15-induced lysosomal biogenesis further facilitated lysosomal GPX4 degradation via chaperone-mediated autophagy (CMA), sensitizing cancer cells to ferroptosis. Furthermore, drug-resistant cancer cells (Taxol-resistant A549 cells and gefitinib-resistant PC9 cells), including both p53-proficient and p53-deficient cells, were vulnerable to Hdj-15-mediated GPX4 inhibition. In xenograft tumor models, Hdj-15 suppressed tumor growth in vivo. In summary, elucidating the molecular mechanisms of the novel ferroptosis inducer Hdj-15 demonstrated that the interplay between the ER and lysosomes plays a critical role in shaping ferroptotic cell death, which in turn sensitizes drug-resistant cancer cells.

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