Medium-Chain Fatty Acids Selectively Sensitize Cancer Cells to Ferroptosis by Inducing CD36 and ACSL4

Inducing ferroptosis in cancer cells is a promising therapeutic strategy. It has been shown that certain types of fatty acids can induce ferroptosis in multiple types of cancer cells.

Here, we employed crystal violet staining and CCK8 to assess cell viability, a Liperfluo probe and commercial kit to measure lipid peroxides, and western blotting and RNA interference to detect protein levels.

This study demonstrates for the first time that the medium-chain fatty acids lauric acid (LA-m), octanoic acid (OA-m), and decanoic acid (DA-m) selectively sensitize various cancer cell types to ferroptosis induced by either RSL3, a well-known inducer of ferroptosis, or linoleic acid (LA-l), a ω-6 polyunsaturated fatty acid (PUFA). Mechanistically, the ferroptosis-sensitizing effect of medium-chain fatty acids is associated with their ability to upregulate cluster of differentiation 36 (CD36) and acyl-CoA synthetase long-chain family member 4 (ACSL4) expression.

These findings suggest that medium-chain fatty acids could be developed as novel ferroptosis sensitizers to enhance ferroptosis-based cancer therapy.