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Biosci. (Landmark Ed)"],"abstract":"<jats:p>Background: Acute lung injury (ALI) triggered by sepsis continues to pose a significant difficulty in clinical practice. Due to its anti-inflammatory and antioxidant activities, calcitonin is considered a potential therapeutic option in sepsis. Methods: Bioinformatics analysis was performed using the GSE89376 and GSE67652 datasets. Serum levels of CD3D and NLR family pyrin domain containing 3 (NLRP3) inflammasome, as well as high-mobility group box 1 (HMGB1)\/myeloid differentiation primary response gene 88 (MyD88)\/nuclear factor-\u03baB (NF-\u03baB) pathway components, were evaluated in sepsis\/ALI patients. The effects of calcitonin and CD3D knockdown on human pulmonary microvascular endothelial cells (hPMECs) activated by lipopolysaccharide (LPS) were investigated in vitro. Experimental assays, including quantitative real-time polymerase chain reaction (qRT-PCR), Cell Counting Kit-8 (CCK-8) assay, western blotting (WB), enzyme-linked immunosorbent assay (ELISA), and flow cytometry, were used to assess cell viability, apoptosis, cell cycle, and oxidative stress markers. Results: CD3D was identified as a key sepsis\/ALI-associated hub gene and correlated with NF-\u03baB pathway activation in patients. CD3D silencing in hPMECs effectively suppressed LPS-induced inflammation, oxidative stress, apoptosis, and G1 phase arrest by downregulating the expression of NLRP3, phosphorylation (p)-NF-\u03baB, MyD88, and HMGB1. Calcitonin alone mitigated LPS-induced injury in a dose-dependent way and further enhanced the protective impacts of CD3D knockdown. Co-treatment resulted in synergistic inhibition of interleukin (IL)-1\u03b2, IL-6, and tumor necrosis factor (TNF)-\u03b1, a reduction in oxidative markers, restoration of antioxidant capacity (superoxide dismutase (SOD) and glutathione (GSH)), improved endothelial cell viability, and attenuation of apoptosis. Notably, combined treatment more robustly suppressed the HMGB1\/MyD88\/NF-\u03baB pathway than either intervention alone. Conclusion: CD3D exacerbates sepsis-induced ALI by potentiating the HMGB1\/MyD88\/NF-\u03baB pathway and NLRP3 inflammasome, driving inflammation and oxidative stress. Combined CD3D knockdown and calcitonin treatment offers a novel synergistic therapeutic strategy for mitigating pulmonary endothelial injury in sepsis.<\/jats:p>","DOI":"10.31083\/fbl44677","type":"journal-article","created":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T02:40:44Z","timestamp":1762483244000},"source":"Crossref","is-referenced-by-count":4,"title":["Calcitonin Alleviates Sepsis-Induced Acute Lung Injury by Inhibiting the HMGB1\/MyD88\/NF-\u03baB Pathway by Targeting CD3D"],"prefix":"10.31083","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-5170-6660","authenticated-orcid":true,"given":"Hongyan","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Critical Care Medicine, The Third Affiliated Hospital of Naval Medical University, 201805 Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3932-4026","authenticated-orcid":true,"given":"Ruiqing","family":"Zong","sequence":"first","affiliation":[{"name":"Department of Critical Care Medicine, The Third Affiliated Hospital of Naval Medical University, 201805 Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1060-1672","authenticated-orcid":true,"given":"Huiqi","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Critical Care Medicine, The Third Affiliated Hospital of Naval Medical University, 201805 Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3404-2071","authenticated-orcid":true,"given":"Jun","family":"Jiang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Genetic Engineering, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences, Fudan University, 200438 Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3370-2295","authenticated-orcid":true,"given":"Jian","family":"He","sequence":"first","affiliation":[{"name":"Department of Critical Care Medicine and Emergency Medicine, The Third Affiliated Hospital of Naval Medical University, 201805 Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2025,10,28]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Ibarz M, Haas LEM, Ceccato A, Artigas A. 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