Neural Regeneration Research ›› 2026, Vol. 21 ›› Issue (2): 756-768.doi: 10.4103/NRR.NRR-D-24-00999

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Fibrotic scar formation after cerebral ischemic stroke: Targeting the Sonic hedgehog signaling pathway for scar reduction

Jun Wen1, #, Hao Tang1, #, Mingfen Tian1 , Ling Wang1 , Qinghuan Yang1 , Yong Zhao1 , Xuemei Li2 , Yu Ren1 , Jiani Wang1 , Li Zhou1 , Yongjun Tan1 , Haiyun Wu1 , Xinrui Cai1 , Yilin Wang1 , Hui Cao3 , Jianfeng Xu3 , Qin Yang1, *   

  1. 1 Department of Neurology, The Frist Affiliated Hospital of Chongqing Medical University, Chongqing, China;  2 Department of Neurology, Second People’s Hospital of Chongqing Banan District, Chongqing, China;  3 Department of Neurosurgery, Third Hospital of Mianyang, Mianyang, Sichuan Province, China
  • Online:2026-02-15 Published:2025-05-24
  • Contact: Qin Yang, MD, PhD, xyqh200@126.com.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, Nos. 82171456 (to QY) and 81971229 (to QY); the Natural Science Foundation of Chongqing, Nos. CSTC2021JCYJ-MSXMX0263 (to QY) and CSTB2023NSCQ-MSX1015 (to XL); Doctoral Innovation Project of The First Affiliated Hospital of Chongqing Medical University, Nos. CYYY-BSYJSCXXM-202318 (to JW) and CYYY-BSYJSCXXM-202327 (to HT).

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Abstract: Recent studies have shown that fibrotic scar formation following cerebral ischemic injury has varying effects depending on the microenvironment. However, little is known about how fibrosis is induced and regulated after cerebral ischemic injury. Sonic hedgehog signaling participates in fibrosis in the heart, liver, lung, and kidney. Whether Shh signaling modulates fibrotic scar formation after cerebral ischemic stroke and the underlying mechanisms are unclear. In this study, we found that Sonic Hedgehog expression was upregulated in patients with acute ischemic stroke and in a middle cerebral artery occlusion/reperfusion injury rat model. Both Sonic hedgehog and Mitofusin 2 showed increased expression in the middle cerebral artery occlusion rat model and in vitro fibrosis cell model induced by transforming growth factor-beta 1. Activation of the Sonic hedgehog signaling pathway enhanced the expression of phosphorylated Smad 3 and Mitofusin 2 proteins, promoted the formation of fibrotic scars, protected synapses or promoted synaptogenesis, alleviated neurological deficits following middle cerebral artery occlusion/reperfusion injury, reduced cell apoptosis, facilitated the transformation of meninges fibroblasts into myofibroblasts, and enhanced the proliferation and migration of meninges fibroblasts. The Smad3 phosphorylation inhibitor SIS3 reversed the effects induced by Sonic hedgehog signaling pathway activation. Bioinformatics analysis revealed significant correlations between Sonic hedgehog and Smad3, between Sonic hedgehog and Mitofusin 2, and between Smad3 and Mitofusin 2. These findings suggest that Sonic hedgehog signaling may influence Mitofusin 2 expression by regulating Smad3 phosphorylation, thereby modulating the formation of early fibrotic scars following cerebral ischemic stroke and affecting prognosis. The Sonic Hedgehog signaling pathway may serve as a new therapeutic target for stroke treatment.

Key words: central nervous system, fibroblasts, fibrosis, ischemic stroke, Mitofusin 2, middle cerebral artery occlusion/reperfusion, P-Smad3, Sonic Hedgehog, Smad3, TOM20