Kaempferol Restores Cilia Length Through Axonemal Microtubule Stabilization

Abstract

Ciliary shortening disrupts cilium-dependent signaling and tissue homeostasis and contributes to diverse ciliopathies and acquired disorders. However, the underlying mechanisms and pharmacological strategies for restoring ciliary length remain poorly understood. Here, we identify Kaempferol (Kae) as a previously unrecognized small-molecule regulator of ciliary length. Transcriptomic profiling showed that Kae-responsive genes were enriched in cytoskeleton- and microtubule-related processes, including microtubule organization and motor protein activity, suggesting that cytoskeletal regulation may contribute to its effects on ciliary length. Further investigation demonstrated that Kae promoted ciliary elongation under basal conditions and restored ciliary length across mechanistically distinct defect models, including SARS-CoV-2 non-structural protein 13 (NSP13) expression, Ciliobrevin D-mediated dynein inhibition, and centrosomal protein 290 (CEP290) deficiency. Mechanistically, Kae enhanced microtubule stability, as indicated by increased acetylated α-tubulin (ACTUB) expression, greater resistance to nocodazole-induced depolymerization, and enhanced microtubule recovery. Consistent with these cellular effects, Kae promoted microtubule recovery and preserved ciliary ultrastructure in the NSP13-induced airway injury model in vivo. These findings establish Kae as a pharmacological modulator of ciliary length and highlight axonemal microtubule stabilization as a potential strategy for restoring dysfunctional cilia.