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Emerging evidence highlights hydrogen sulfide (H2S) as a gasotransmitter modulating redox balance, autophagy, and apoptosis. This study investigates the neuroprotective mechanisms of Enriched Environment (EE) against ischemic injury, focusing on mitochondrial dynamics and H2S-mediated pathways. Using MCAO mice and OGD\/R-treated SH-SY5Y neurons, interventions targeting H2S synthesis, hypoxia-inducible factor 1-alpha (HIF-1\u03b1), and mitophagy were implemented. Behavioral, histological, and molecular analyses demonstrated EE significantly improved neurological outcomes, suppressed apoptosis, and attenuated oxidative damage (reduced MDA, elevated MnSOD\/glutathione). Mechanistically, EE enhanced mitophagy via dual pathways: canonical PINK1\/parkin-mediated mitochondrial clearance, corroborated by transmission electron microscope and LC3B\/parkin colocalization, and non-canonical HIF-1\u03b1\/BNIP3L axis activation. Transcriptomic and Co-immunoprecipitation (Co-IP) data revealed EE upregulated endogenous H2S biosynthesis post-injury by promoting dopamine-induced calcium influx, which activated calmodulin-dependent signaling to stimulate cystathionine \u03b2-synthase\/\u03b3-lyase expression. Pharmacological blockade of H2S synthesis or HIF-1\u03b1 abolished mitochondrial protection, confirming H2S as a central mediator. Notably, H2S exerted antiapoptotic effects by restoring mitochondrial integrity through synergistic mitophagy activation and oxidative stress mitigation. These findings propose a novel neuroprotective cascade: EE-induced dopaminergic signaling potentiates H2S production, which coordinates PINK1\/parkin and HIF-1\u03b1\/BNIP3L pathways to eliminate dysfunctional mitochondria, thereby preserving neuronal homeostasis. This study elucidates therapeutic potential of EE via H2S-driven mitochondrial quality control, offering insights for ischemic brain injury intervention.<\/jats:p>","DOI":"10.3390\/antiox15010052","type":"journal-article","created":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T16:34:23Z","timestamp":1767198863000},"page":"52","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Enriched Environment Ameliorates Cerebral Ischemia\u2013Reperfusion Injury via Dopamine\u2013H2S Axis-Mediated Dual Mitophagy Activation"],"prefix":"10.3390","volume":"15","author":[{"given":"Bao","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haocheng","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6371-0765","authenticated-orcid":false,"given":"Pengkun","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengran","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhong","family":"He","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zijian","family":"Hua","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ce","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shenyi","family":"Kuang","sequence":"additional","affiliation":[{"name":"National Center for Neurological Disorders, Shanghai 200040, China"},{"name":"Department of Neurology, Huashan Hospital, Fudan University, Shanghai 200040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulian","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China"},{"name":"National Center for Neurological Disorders, Shanghai 200040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kewei","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China"},{"name":"National Center for Neurological Disorders, Shanghai 200040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1177\/17474930241308142","article-title":"World Stroke Organization: Global Stroke Fact Sheet 2025","volume":"20","author":"Feigin","year":"2025","journal-title":"Int. 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