BAP31 protects against acute lung injury by suppressing ferroptosis via the AKT/GSK3β/Nrf2 pathway

Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), remain life-threatening conditions with mortality rates around 40%, despite advances in mechanical ventilation and corticosteroid therapy. Damage to type II alveolar epithelial cells (AEC II) is a critical pathological feature of ALI, driven by oxidative stress, apoptosis, and inflammation. Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation and glutathione depletion, has emerged as a key contributor to ALI progression. However, effective therapeutic strategies targeting ferroptosis in ALI are still lacking.

A recent study led by researchers from the Chinese PLA General Hospital has uncovered a novel protective mechanism involving B-cell receptor-associated protein 31 (BAP31), an endoplasmic reticulum integral membrane protein. The study, which was made available online on January 23, 2026, and published in Volume 246 on March 16, 2026, in the Chinese Medical Journal, investigated the relationship between BAP31 and ferroptosis in LPS-induced ALI using both wild-type and Sftpc-BAP31 transgenic mice, as well as MLE-12 and BEAS-2B alveolar epithelial cell lines.

The researchers first established that ferroptosis is a critical driver of ALI progression. In LPS-challenged mice, lung tissues exhibited characteristic ferroptotic features, including iron overload, malondialdehyde (MDA) accumulation, glutathione (GSH) depletion, and reduced GPX4 expression. Electron microscopy confirmed mitochondrial ultrastructural damage typical of ferroptosis. Treatment with the ferroptosis inhibitor ferrostatin-1 (Fer-1) effectively alleviated these biochemical and morphological defects, while also reducing lung injury and proinflammatory cytokine production. Similar results were observed in LPS-exposed MLE-12 cells, where Fer-1 restored cell viability and reversed ferroptosis markers.

Notably, the study found that BAP31 expression was significantly downregulated in lung tissues following LPS challenge in a time-dependent manner. To explore BAP31's protective role, the researchers generated Sftpc-BAP31 transgenic mice. Overexpression of BAP31 markedly reduced LPS-induced inflammatory responses, as evidenced by decreased levels of IL-1β, IL-6, and TNF-α in bronchoalveolar lavage fluid (BALF). Additionally, BAP31 overexpression attenuated elevated total cell counts and neutrophil infiltration, mitigated pulmonary vascular permeability, and improved lung histopathology. Survival analysis further demonstrated that BAP31 transgenic mice exhibited significantly higher survival rates than wild-type controls.

Transcriptomic analysis of lung tissues from BAP31 transgenic and wild-type mice following LPS treatment identified 1,657 differentially expressed genes, with KEGG pathway analysis revealing ferroptosis as a predominantly enriched pathway. In both in vivo and in vitro experiments, BAP31 overexpression reversed LPS-induced alterations in ferroptosis markers, including reduced MDA and reactive oxygen species (ROS) accumulation, restored GSH levels, and enhanced expression of GPX4 and HO-1.

Mechanistically, the study elucidated that BAP31 inhibits ferroptosis by promoting nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). Western blot analysis showed increased nuclear Nrf2 levels in BAP31-overexpressing MLE-12 cells following LPS treatment. Inhibition of Nrf2 using ML385 restored ferroptosis in these cells, confirming Nrf2's essential role. Further investigation revealed that BAP31 enhances phosphorylation of GSK3β at Ser9, thereby reducing GSK3β-mediated Nrf2 degradation. Inhibition of GSK3β with CT99021 attenuated BAP31's protective effects against ferroptosis.

The researchers further demonstrated that BAP31 promotes GSK3β phosphorylation via the AKT pathway. LPS treatment increased phosphorylated AKT (Thr308) levels in BAP31 transgenic mice compared with wild-type mice. Inhibition of AKT with MK2206 in BAP31-overexpressing cells significantly reduced GSK3β phosphorylation, suppressed Nrf2 nuclear translocation, and restored cellular ferroptosis. These findings were consistently replicated in human bronchial epithelial BEAS-2B cells. In vivo experiments using BAP31 transgenic mice treated with MK2206 confirmed that inhibition of the AKT pathway exacerbated lung tissue damage, increased inflammatory cell infiltration, and elevated proinflammatory cytokine levels following LPS challenge.

The study concludes that BAP31 mitigates acute lung injury by inhibiting ferroptosis through activation of the AKT/GSK3β/Nrf2 pathway in alveolar epithelial cells. This protective axis promotes the transcription of ferroptosis-related genes, including GPX4 and HO-1, thereby reducing lipid peroxidation and oxidative stress. The authors acknowledge several limitations, including the lack of functional rescue experiments with BAP31 knockdown, absence of clinical sample validation, and the use of only male mice. Future studies incorporating clinical validation and rigorous rescue assays are needed to further solidify the translational potential of targeting BAP31 in ALI.

These findings offer new insights into the molecular mechanisms underlying ALI and suggest that BAP31 and its downstream signaling components may serve as promising therapeutic targets for acute lung injury and acute respiratory distress syndrome.

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Reference
Title of original paper: BAP31 Protects Against Acute Lung Injury by Suppressing Ferroptosis via the AKT/GSK3β/Nrf2 Pathway

Journal: Chinese Medical Journal

DOI: 10.1097/CM9.0000000000004223

About the Authors
Pingjun Zhu – Department of Respiratory and Critical Care Medicine, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing 100853, China. Email: zhupingjun@301hospital.org

Guogang Xu – Health Management Institute, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing 100853, China. Email: guxu@301hospital.org

Yingzhen Du – Department of Disease Control and Prevention, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing 100853, China; Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing 100853, China. Email: zhenzhen52@163.com

Funding information
This research was supported by the University-City Joint General Project of Guangzhou Science and Technology Bureau (2024A03J0066)