Capsanthin Attenuates Osteoporosis by Targeting the Urotensin II Receptor Pathway to Inhibit Oxidative Stress and NLRP3 Inflammasome Activation.

Abstract

Although multiple pharmacological options exist for postmenopausal osteoporosis (PMOP), the pursuit of better-tolerated and naturally derived alternatives remains active. This study evaluates the therapeutic potential of capsanthin (Cap), the principal carotenoid in red chili peppers, against estrogen deficiency-induced bone loss. Ovariectomized (OVX) mice were treated with Cap (5-20 mg/kg/day) for 12 weeks. Bone mass and microarchitecture were assessed by micro-computed tomography (µCT) and biomechanical testing. Serum markers of bone turnover and inflammation were measured by ELISA. Network pharmacology and molecular docking were employed to predict core targets, and the involvement of the urotensin II (UII) system and NLRP3 inflammasome was investigated using specific inhibitors in vitro. Cap treatment at 10-20 mg/kg significantly attenuated OVX-induced bone loss, increasing bone mineral density (BMD), improving trabecular microstructure (elevated BV/TV and Tb.Th, reduced Tb.Sp), and enhancing bone strength. Cap promoted osteogenic activity and suppressed osteoclastic resorption. Network analysis identified the UII signaling pathway as a key potential target, and molecular docking confirmed strong binding between Cap and UII. Mechanistically, Cap inhibited the UII/UT axis, leading to reduced oxidative stress (decreased ROS/H₂O₂, increased MnSOD) and suppression of NLRP3 inflammasome activation and pyroptosis, as evidenced by downregulation of NLRP3, caspase-1, IL-1β, and GSDMD. The osteoprotective effects of Cap were mimicked by UT receptor knockdown or NLRP3 inhibition in osteoblastic cells. Cap exerts protective effects against OVX-induced osteoporosis by promoting bone formation and inhibiting bone resorption. Its mechanism involves, at least in part, the inhibition of the UII/UT signaling pathway, which subsequently attenuates oxidative stress and NLRP3-mediated pyroptosis. These findings highlight cap as a promising natural candidate for further development in the management of osteoporosis.