Omega-3 Fatty Acid DHA Induces Ferroptosis in Colorectal Cancer Patient-Derived Organoids and Drug-Tolerant Cells

Several epidemiological and preclinical studies suggest that omega-3 (n-3) polyunsaturated fatty acids (PUFAs) exert anticancer activity at multiple stages of colorectal cancer (CRC) progression. However, inconsistent clinical evidence and the lack of a defined molecular mechanism underlying the antitumoral effects of n-3 PUFAs have raised doubts about their efficacy as adjuvant anticancer therapies. To address these issues, we investigated the effects of the n-3 PUFA docosahexaenoic acid (DHA) in a collection of CRC patient-derived tumor organoids (PDTOs), a powerful platform for functional analysis of patient-specific tumors. DHA treatment markedly reduced CRC cell viability in a time- and concentration-dependent manner without activating apoptosis. CRC-derived PDTOs exhibited pronounced sensitivity to DHA, irrespective of KRAS or TP53 mutational status, whereas organoids from normal colon tissue were less affected. Mechanistically, DHA induced ferroptosis in both CRC cells and PDTOs, as evidenced by lipid peroxide accumulation and partial rescue by ferroptosis inhibitors. Fluorescently labeled DHA localized predominantly to the endoplasmic reticulum and mitochondria, where it promoted oxidative stress. Moreover, DHA impaired the regrowth of oxaliplatin-tolerant persister cells and enhanced oxaliplatin efficacy in sequential treatment models. Together, these findings indicate that exploiting the intrinsic oxidative vulnerability of cancer cells with DHA may represent a promising, low-toxicity strategy to enhance chemotherapy efficacy and target drug-tolerant persister cells in colorectal cancer.