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Neuroinflammation, a hallmark of RP, is largely driven by microglial activation and amplified when cells are primed by oxidative stress. Store-operated calcium entry (SOCE), primarily mediated by Orai1 channels, regulates microglial metabolism and inflammatory signaling. Here, we tested whether ethanol (EtOH) exacerbates RP-related neuroinflammation through SOCE-dependent mechanisms and whether 2-aminoethoxydiphenyl borate (2-APB) mitigates these effects. In mixed retinal cultures, a \u201cdouble-hit\u201d (oxidative stress + EtOH) triggered pronounced microglial activation, neuronal loss, and altered cytokine expression and correlation patterns, assessed by multiplex bead assays and hierarchical clustering analysis. Indeed, 2-APB restored ramified morphology and improved neuronal survival. Conditioned medium experiments revealed that both microglia and M\u00fcller cells responded to the double-hit, but only microglia were sensitive to SOCE inhibition. In vivo, subretinal delivery of EtOH and 2-APB in rd1 mice, a genetic model of RP, altered microglial morphology and reduced pro-inflammatory cytokine levels without affecting photoreceptor density. Notably, in situ assessment of CD86\/CD206 showed no change in expression, indicating that microglial activation in vivo is better captured by morphological and cytokine-network alterations than by classical surface markers. These findings show that alcohol misuse amplifies retinal neuroinflammation in RP via calcium-dependent mechanisms and identify SOCE as a therapeutic target for limiting damage from systemic comorbidities in retinal degeneration.<\/jats:p>","DOI":"10.1038\/s41420-026-03074-2","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T14:59:54Z","timestamp":1774969194000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Store-operated calcium entry drives alcohol-exacerbated neuroinflammation in retinal degeneration"],"prefix":"10.1038","volume":"12","author":[{"given":"Th\u00e9o Henrique de","family":"Lima-Vasconcellos","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bruna de Albuquerque","family":"Menezes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00edlia In\u00eas","family":"M\u00f3vio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabrieli","family":"Bovi dos Santos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriela Maria","family":"Badin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William","family":"Silva","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4027-7261","authenticated-orcid":false,"given":"Alexandre Hiroaki","family":"Kihara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,3,31]]},"reference":[{"key":"3074_CR1","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1177\/2474126420936455","volume":"5","author":"P Le","year":"2020","unstructured":"Le P, Nguyen M, Vu T, Dao DP, Olson D, Zhang AY. 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