{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T19:44:00Z","timestamp":1793043840008,"version":"4.5.0"},"reference-count":30,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T00:00:00Z","timestamp":1750118400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Key R&amp;D Projects of Science and Technology Department of Sichuan Province","award":["Grant number 2023YFS0025"],"award-info":[{"award-number":["Grant number 2023YFS0025"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Background: Sepsis-induced acute lung injury (ALI) is a serious disease constituting a heavy burden on society due to high mortality and morbidity. Inflammation and oxidative stress constitute key pathological mechanisms in ALI caused by sepsis. LL-37 can improve the survival of septic mice. Nevertheless, its function and underlying mechanism in sepsis-evoked ALI is elusive. Methods: The human A549 alveolar epithelial cell line was treated with LL-37 or ZBP1 recombinant vector under LPS exposure. Then, the effects on cell oxidative stress injury, inflammatory response, and autophagy were analyzed. RNA-seq analysis was performed to detect the differentially expressed genes (DEGs) between the LPS and LPS\/LL-37 groups. Furthermore, the effects of LL-37 on cecal ligation and the puncture (CLP)-constructed ALI model were explored. Results: LL-37 attenuated LPS-evoked oxidative injury in human alveolar epithelial cells by increasing cell viability and suppressing ROS, malondialdehyde, and lactate dehydrogenase levels and apoptosis. Moreover, LPS-induced releases of pro-inflammatory IL-18, TNF-\u03b1, and IL-1\u03b2 were suppressed by LL-37. Furthermore, LPS\u2019s impairment of autophagy was reversed by LL-37. RNA-seq analysis substantiated 1350 differentially expressed genes between the LPS and LPS\/LL-37 groups. Among them was ZBP1, a significantly down-regulated gene with the largest fold change. Moreover, LL-37 suppressed LPS-increased ZBP1 expression. Importantly, ZBP1 elevation restrained LL-37-induced autophagy in LPS-treated cells and abrogated LL-37-mediated protection against LPS-evoked oxidative injury and inflammation. LL-37 ameliorated abnormal histopathological changes, tissue edema, the lung injury score, oxygenation index (PaO2\/FiO2), and glycemia contents in the CLP-constructed ALI model, which were offset through ZBP1 elevation via its activator CBL0137. Additionally, LL-37 suppressed inflammation and oxidative stress in lung tissues, concomitant with autophagy elevation and ZBP1 down-regulation. Conclusions: LL-37 may alleviate the progression of sepsis-evoked ALI by attenuating pulmonary epithelial cell oxidative injury and inflammatory response via ZBP1-mediated autophagy activation, indicating a promising approach for the therapy of ALI patients.<\/jats:p>","DOI":"10.3390\/toxins17060306","type":"journal-article","created":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T03:37:07Z","timestamp":1750131427000},"page":"306","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["LL-37 Attenuates Sepsis-Induced Lung Injury by Alleviating Inflammatory Response and Epithelial Cell Oxidative Injury via ZBP1-Mediated Autophagy"],"prefix":"10.3390","volume":"17","author":[{"given":"Hu","family":"Gao","sequence":"first","affiliation":[{"name":"Department of Emergency Medicine, West China Second University Hospital, Sichuan University, Chengdu 610041, China"},{"name":"Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fajuan","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, West China Second University Hospital, Sichuan University, Chengdu 610041, China"},{"name":"Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, West China Second University Hospital, Sichuan University, Chengdu 610041, China"},{"name":"Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xihong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, West China Second University Hospital, Sichuan University, Chengdu 610041, China"},{"name":"Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,17]]},"reference":[{"key":"ref_1","first-page":"1","article-title":"Trends in inpatient hospital deaths: National Hospital Discharge Survey, 2000\u20132010","volume":"118","author":"Hall","year":"2013","journal-title":"NCHS Data Brief."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1111\/bju.16029","article-title":"Sepsis prevalence and associated hospital admission and mortality after ureteroscopy in employed adults","volume":"132","author":"Bhojani","year":"2023","journal-title":"BJU Int."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Lei, S., Li, X., Zhao, H., Xie, Y., and Li, J. 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