Dual-PPARα/δ agonist H11 alleviates tendinopathy via modulating the Nrf2/HO-1/GPX4 pathway.

Tendinopathy, a prevalent degenerative musculoskeletal disorder, remains a therapeutic challenge due to limited efficacy of existing treatments. Oxidative stress and ferroptosis are pivotal pathological mechanisms in tendinopathy, which are linked to dysregulation of the NRF2/HO-1/GPX4 pathway. This study investigates the therapeutic potential of H11, a dual-PPARα/δ agonist, in mitigating tendinopathy via modulating this pathway. Clinical analysis of human tendinopathic tissues revealed downregulated PPARα/δ and aberrant NRF2/HO-1/GPX4 expression. In vitro, H11 dose-dependently activated PPAR subtypes, alleviated TBHP(tert-butyl hydroperoxide)-induced oxidative stress, and restored mitochondrial membrane potential in Achilles tendon cells. Co-treatment with PPAR subtype-specific inhibitors (GW6471, GSK0660) partially attenuated H11's protective effects, while single-subunit agonists (GW7647, GW50526) showed inferior efficacy compared to H11. NRF2 silencing via siRNA abolished H11-mediated therapeutic outcomes, confirming NRF2's indispensable role. In a collagenase-induced rat tendinopathy model, H11 restored collagen organization, reduced malondialdehyde (MDA) levels, and enhanced glutathione (GSH/GSSG) ratios, concomitant with upregulated PPARα/δ and NRF2/HO-1/GPX4 expression. These results indicate that the PPARα/δ dual-agonist H11 ameliorates tendinopathy by activating PPARα/δ, enhancing antioxidant capacity, and inhibiting ferroptosis via the NRF2/HO-1/GPX4 axis.