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

Background: 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.

Methods: 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.

Results: 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.

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