ER-resident sirtuin confers chemosensitivity by shifting iron metabolism

Chemotherapy is a major cancer therapeutic strategy worldwide, yet the frequently occurred chemoresistance remains an unsolved challenge1,2. Although extensive efforts have been devoted to this issue3,4, an unbiased functional examination of causal factors for chemoresistance is currently lacking5,6. Here we performed multiple genome-scale functional screens in gastrointestinal cancer cells, and identified the protein deacetylase SIRT2 as a key determinant of chemosensitivity. Intriguingly, chemoresistant tumor cells and tissues exhibit attenuated expression of SIRT2.2, an underappreciated splicing isoform of SIRT2 enriched in the endoplasmic reticulum (ER). SIRT2.2 confers chemosensitivity by targeting TFRC, a membrane receptor mediating the uptake of extracellular ferric iron. SIRT2.2-elicited TFRC deacetylation safeguards the interaction between TFRC and the metalloreductase STEAP4, promotes the reduction of ferric to ferrous iron in acidic endolysosomes, leading to enhanced ferroptosis in cancer cells challenged by chemotherapeutics. We then utilized autochthonous murine models to demonstrate that genetically restored SIRT2.2 expression synergized with chemotherapy to induce robust tumoral ferroptosis and profound tumor regression, which were recapitulated in patient-derived xenograft mouse models fed with an iron-rich diet. Additionally, cancer patients with high iron stores were more responsive to chemotherapy, indicating that dietary approaches to enhance iron accumulation represent promising strategies to clinically improve the chemotherapeutic efficacy.