STAT6 inhibits ferroptosis and alleviates acute lung injury via regulating P53/SLC7A11 pathway

Abstract

Compelling evidences have revealed the emerging role of ferroptosis in the pathophysiological process of acute lung injury (ALI), but its modulation is not clear. Here, we identified that STAT6 acted as a critical regulator of epithelium ferroptosis during ALI. Firstly, STAT6 expression and activity were increased in the ALI mice models caused by crystalline silica (CS), LPS and X-ray exposure. Followed by confirming the contribution of ferroptosis in the above ALI with ferrostatin-1 and deferoxamine intervention, bioinformatic analyses revealed that STAT6 expression was negatively correlated with ferroptosis. Consistently, lung epithelium-specific depletion of STAT6 in mice or STAT6 knockdown in cultured epithelial cells exacerbated ferroptosis in the above ALI. While overexpression of STAT6 in lung epithelial cells attenuated the ferroptosis. Mechanistically, SLC7A11 is a typical ferroptosis-related gene and negatively regulated by P53. CREB-binding protein (CBP) is a critical acetyltransferase of P53 acetylation, showing valuable regulation on targets’ transcription. Herein, we found that STAT6 negatively regulates ferroptosis through competitively binding with CBP, which inhibits P53 acetylation and transcriptionally restores SLC7A11 expression. Finally, pulmonary-specific STAT6 overexpression decreased the ferroptosis and attenuated CS and LPS induced lung injury. Our findings revealed that STAT6 is a pivotal regulator of ferroptosis, which may be a potential therapeutic target for the treatment of acute lung injury.

WITHDRAWN: Resveratrol inhibits ferroptosis and decelerates heart failure progression via Sirt1/p53 pathway activation

“…An acetylation defective mutant P53 with 3 mutated lysine residues (K117/161/162R) fails to induce apoptosis and senescence, but still sensitized cells to ferroptosis [35,36]. Yang et al found that STAT6 alleviated acute lung injury by regulating the P53/SLC7A11 pathway to inhibit ferroptosis [37]. Sirt1 has been shown to reduce the acetylation of p53 K382 to prevent cell senescence and atherosclerosis [21].…”

IRF8 Regulates Intrinsic Ferroptosis through Repressing p53 Expression to Maintain Tumor Cell Sensitivity to Cytotoxic T Lymphocytes

“…p53 has dual and opposite functions in ferroptosis and its function in regulating ferroptosis is apparently cellular context-dependent [26][27][28][29][30][31][32][33]. It has been shown that p53 represses SLC7A11 to induce extrinsic ferroptosis, which releases arachidonate 12-Lipoxygenase, 12S type (ALOX12) from SLC7A11 inhibition [27].…”

“…Therefore, in addition to the Fas-FasL and granzyme B-perforin pathways, ferroptosis is another CTL-mediated cell death pathway that may also contributes to the CTL effector function in ICI immunotherapy [25]. p53 is a key regulator of ferroptosis and can either promote or suppress ferroptosis by cellular context-dependent mechanisms [26][27][28][29][30][31][32][33]. How p53 is regulated in the ferroptosis pathway is currently incompletely understood.…”

Recent findings on the role of wild-type and mutant p53 in cancer development and therapy

“…Studies have shown that ferroptosis inducers (FINs) that inhibit SLC7A11 display significant radiation sensitizing effects on tumor organoids and xenografts derived from patients with p53 deficiency or mutation. Accordingly, activation of p53 and RT-induced ferroptosis leads to better clinical outcomes for RT in cancer patients, and it is suggested that these FINs be used in combination with radiotherapy to treat p53 mutant cancers ( Lei et al, 2021 ; Yang et al, 2022 ).…”