Intestinal Absorption of Dietary Astaxanthin Mediated by Cluster-Determinant 36 (CD36) Presents Stereoisomeric Selectivity In Vitro and In Vivo

Astaxanthin exists as multiple stereoisomers owing to chiral carbons, with (3 S,3′ S ) ( S ) and (3 R,3′ R ) ( R ) as the major natural enantiomer. The differential bioactivity of these isomers implies potential stereoselective absorption. However, whether cluster-determinant 36 (CD36), a key transporter of astaxanthin, exhibits such stereospecificity remains unclear. Herein, molecular docking and alanine scanning mutagenesis revealed a higher affinity (ΔΔ G = −1.39 kcal/mol) of ( S )-astaxanthin for CD36, attributed to a unique hydrogen bond with ASN53 and critical interactions with PHE300, LEU328, and PHE430. Subsequent CD36-overexpressing cells showed 14.44% higher ( S )-enantiomer uptake than ( R )-counterpart ( P < 0.05). In situ model further revealed superior absorption rate and permeability for ( S )-astaxanthin. Critically, the CD36-specific inhibitor sulfo- N -succinimidyl oleate considerably inhibited ( S )-astaxanthin absorption in the duodenum and jejunum by 83.78 and 84.01%, respectively, which were notably higher than the inhibitions of ( R )-form (49.16 and 36.24%, P < 0.01). This work provides the first evidence that CD36 mediates stereospecific ( S )-astaxanthin transport, advancing chiral carotenoid research.