Branched-chain fatty acids with different structure exhibit distinct anti-hepatoma activities and characteristics

Branched-chain fatty acids (BCFAs) exhibit potential anticancer activity, but their systematic evaluation and comparison with straight-chain saturated fatty acids (SSFAs) remain limited due to monomer accessibility issues. This study utilized lanolin, a rich BCFA/SSFA mixture, to systematically assess anti-hepatoma activities of 50 fatty acids using multiple linear regression (MLR) and orthogonal partial least squares (OPLS) models combined with HepG2 cell viability, apoptosis, and cell cycle assays. MLR identified iso-C13:0 as a unique protective fatty acid, while OPLS revealed strong explanatory power (R2X = 0.827-0.997, R2Y = 0.718-0.782) and key anti-hepatoma fatty acids, including SSFAs (C12:0, C13:0, C14:0, C19:0, C21:0) and BCFAs (16-19-carbon iso-BCFAs, 14-19-carbon anteiso-BCFAs). Notably, SSFAs outperformed BCFAs in certain activities, and a structure-activity trend emerged: odd-carbon BCFAs favored cell cycle arrest, even-carbon BCFAs promoted apoptosis, and 13-21-carbon fatty acids showed stronger activity. The integrated approach validated lanolin as an ideal matrix for functional lipid screening, providing a methodology to identify anticancer fatty acids in complex mixtures and challenging the conventional superiority of BCFAs.