ACSL6 modulates docosahexaenoic acid-induced cytotoxicity to potentiate chemotherapy response in colorectal and breast cancer.

Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid, exhibits anticancer properties by modulating cell membrane composition, inducing oxidative stress, and triggering ferroptosis. Acyl-CoA synthetase long chain family member 6 (ACSL6) catalyzes DHA activation, yet its role in tumor growth and tumor sensitivity to DHA treatment remains unclear. We characterized the role of ACSL6 in regulating cell growth and DHA sensitivity in vitro cancer cells and in vivo xenograft tumors. ACSL6 expression was positively associated DHA sensitivity and enhanced chemotherapy efficacy in both colorectal and breast cancer cell lines, as well as with improved responsiveness to standard treatments in patients with these cancers. ACSL6 suppressed cell growth, inhibited AKT/ERK signaling, reduced ATP production, and activated AMPK signaling, supporting its tumor-suppressive role. Importantly, ACSL6 knockdown increased GPX4 expression and colony growth, partially rescuing DHA-induced suppression, whereas ACSL6 overexpression enhanced DHA-mediated GPX4 reduction and colony inhibition, effects reversible by RSL3 or ferrostatin-1. Moreover, ACSL6 enhances DHA-induced lipid peroxidation. These support that ACSL6 enhances DHA-induced ferroptosis, leading to growth suppression. In vivo, DHA supplementation potentiated oxaliplatin-suppressed tumor growth in tumors with upregulated ACSL6 expression, accompanied by GPX4 reduction. Together, these findings highlight ACSL6 as a critical determinant of DHA sensitivity in cancer, underscoring its potential as a predictive biomarker for chemotherapy-DHA combination strategies. By modulating key metabolic and signaling pathways, ACSL6 could influence cellular susceptibility to ferroptosis and may guide therapeutic approaches that enhance chemotherapy through DHA supplementation.