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A sustained-release sinomenine hydrogel targets microglial ferroptosis via Nrf2-hmox1 activation to alleviate
Ji Chen1, Lin Zhu2, Yangyuxi Chen3
1Department of Endocrinology, Yuebei People's Hospital, No. 133, South Huimin Road, Shaoguan 512026, Guangdong Province, PR China; Department of Endocrinology, Hunan University of Medicine General Hospital, No. 144, South Jinxi Road, Huaihua 418000, Hunan Province, PR China.
Background:
Sinomenine (SIN), a bioactive alkaloid from Sinomenium acutum, possesses anti-inflammatory properties, but its efficacy against diabetic peripheral neuropathy (DPN) is limited by poor bioavailability and undefined mechanisms.
Purpose:
This study aimed to evaluate the therapeutic effects and mechanism of a SIN-loaded hydrogel (Gel-SIN-M) in DPN.
Methods:
Gel-SIN-M was engineered via crosslinking for controlled SIN delivery. DPN mice received perineural Gel-SIN-M injections. Pain thresholds (von Frey) and motor coordination (gait analysis) were quantified. Intraepidermal nerve fiber density (IENFD), toluidine blue staining, and TEM analyses were used to assess structural recovery. Molecular markers (Nrf2, Hmox1, GPX4, ACSL4) were analyzed by qPCR/Western blot. Ferroptosis inhibition was confirmed in high-glucose-stimulated microglia and further evaluated using RSL3 or ML385 intervention.
Results:
Gel-SIN-M showed excellent biocompatibility and sustained drug release. Treatment significantly improved insulin levels, reduced blood glucose, and alleviated neuropathic pain and motor deficits in DPN mice. It decreased inflammation, restored neurite length, and enhanced nerve fiber density, axon diameter, and myelin thickness. Mechanistically, Gel-SIN-M upregulated Nrf2 and Hmox1, increased GPX4, reduced ACSL4 expression, and suppressed ferroptosis and Fe²⁺ accumulation in microglia. The Nrf2 inhibitor ML385 attenuated these protective effects, supporting the involvement of the Nrf2-Hmox1 axis.
Conclusion:
This study developed a thermosensitive Gel-SIN-M hydrogel that enables sustained, localized drug release in diabetic neuropathic lesions. Gel-SIN-M markedly alleviated neuropathic pain and motor dysfunction in DPN mice through activation of the Nrf2-Hmox1 axis and inhibiting microglial ferroptosis. Importantly, this work is the first to identify microglial ferroptosis as a novel pathogenic mechanism driving DPN progression, and it suggests activation of the Nrf2-Hmox1 axis as a potential multi-target therapeutic strategy integrating antioxidative, anti-inflammatory, and antiferroptotic effects. These findings introduce a new conceptual framework and a promising biomaterial-based approach for the treatment of DPN.
