CH25H-mediated cholesterol metabolism drives chondrogenic differentiation in adipose-derived stem cells and enhances cartilage repair.

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

Cartilage defects are difficult to heal because articular cartilage is both avascular and aneural. Directing adipose-derived mesenchymal stem cells (ADSCs) toward a chondrogenic fate in vitro is regarded as a promising therapeutic strategy. However, the endogenous pathways that specify chondrogenic fate remain incompletely defined. Herein, we identify cholesterol-25-hydroxylase (CH25H) as a key inducer of early chondrogenic differentiation that upregulates the cartilage marker genes SOX9, ACAN, and COL2A1. In ADSCs, FPR1 knockdown and rescue experiments, together with pharmacological inhibition of FPR1 or AKT, supported a signalling model in which 25-HC engages FPR1 to promote AKT/GSK3β pathway activation and chondrogenic differentiation. Surface plasmon resonance assays show that 25-HC directly binds to FPR1 with a dissociation constant of 1.18 µM. Molecular docking and membrane MD/MM/GBSA analyses provided structural context, suggesting stable accommodation of 25-HC in an FPR1 pocket and nominating candidate contacts (including a F81/V105 hydrophobic clamp) for future mutagenesis. In a rat trochlear cartilage-defect model, intra-defect implantation of ADSC-laden hydrogel combined with weekly intra-articular 25-HC dosing was associated with improved repair features, while co-administration of Cyclosporin H/HCH6-1 reduced these benefits. Together, these findings delineate the C

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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