FOSL1 upregulation contributes to ischemia/reperfusion-induced acute kidney injury by regulating GPX4-dependent ferroptosis.

HMGB1/MYH9 suppresses PPARγ to induce lung injury in renal ischemia-reperfusion: protective effects of Rosiglitazone.

METTL3/FOSL1-associated inflammatory and autophagy-related responses involve m6A-related regulation in sepsis-induced acute kidney injury.

BACKGROUND Sepsis-induced acute kidney injury (S-AKI) is marked by tubular damage, inflammation, and dysregulated autophagy. N6-methyladenosine (m6A) RNA modification has emerged as an important regulator of mRNA stability and cellular stress responses; however, its involvement and related regulatory mechanisms in S-AKI remain incompletely understood. METHODS Human HK-2 proximal tubular epithelial cells were stimulated with LPS to establish an in vitro S-AKI model, while CLP-induced septic C57BL/6J mice were used as an in vivo model. Global m6A levels, METTL3, and FOSL1 expression were assessed by ELISA, qRT-PCR, and Western blot. Functional roles of METTL3 and FOSL1 were evaluated using siRNA-mediated knockdown, plasmid-driven overexpression, and pharmacological inhibitors. MeRIP-qPCR and RIP-qPCR were performed to evaluate m6A-related enrichment and the association between METTL3 and FOSL1 mRNA. Inflammatory cytokines, autophagy-related markers, NF-κB and mTOR signaling alterations, renal function, and histopathological changes were assessed. RESULTS LPS stimulation increased global m6A levels and upregulated METTL3 and FOSL1 expression in HK-2 cells, accompanied by enhanced inflammatory responses and autophagy-related alterations. FOSL1 knockdown attenuated LPS-induced inflammation and autophagy-related changes, whereas METTL3 overexpression increased FOSL1 expression and exacerbated these effects. Further analyses indicated that METTL3 was associated with FOSL1 mRNA stability in an m6A-related manner. Alterations in FOSL1 expression were associated with changes in NF-κB and mTOR-related signaling responses under S-AKI conditions. In CLP-induced S-AKI mice, METTL3 knockdown reduced FOSL1 expression, alleviated inflammatory responses and autophagy-related alterations, and improved renal function and histopathological injury. CONCLUSION Our findings suggest that METTL3/FOSL1-associated regulatory responses may participate in S-AKI through m6A-related regulation, contributing to inflammatory and autophagy-related alterations. These findings provide further insight into the involvement of m6A-related regulation in the pathogenesis of S-AKI.

NOV promotes renal ischemia-reperfusion injury by driving TFRC-dependent ferroptosis.

Acute kidney injury (AKI) is a severe clinical syndrome with limited therapeutic options, and its underlying molecular mechanisms remain incompletely understood. Nephroblastoma overexpressed (NOV), a matricellular protein, has been implicated in renal pathophysiology; however, its role in AKI remains unclear. Using a murine renal ischemia-reperfusion (I/R) model and HK-2 cells subjected to hypoxia/reoxygenation (H/R), we found that NOV was rapidly induced in renal tubular epithelial cells (RTECs) during the early phase of AKI. RTEC-specific NOV knockdown significantly alleviated renal dysfunction and tubular injury after I/R. Transcriptomic analysis implicated ferroptosis as a major pathway regulated by NOV. Consistently, NOV knockdown attenuated lipid peroxidation, iron accumulation, and ferroptosis-associated injury both in vivo and in vitro. NOV overexpression increased ferroptotic susceptibility under H/R, and ferrostatin-1 attenuated these effects. Mechanistically, NOV interacted with transferrin receptor (TFRC) and promoted ferroptosis by stabilizing TFRC through reduced K48-linked ubiquitination. NEDD4L was identified as a candidate E3 ligase mediating TFRC ubiquitination, and NOV disrupted NEDD4L-associated K48-linked ubiquitination of TFRC. Collectively, these findings identify the NOV-TFRC axis as a regulator of ferroptotic tubular injury and suggest NOV as a potential therapeutic target in I/R-AKI.

The potential mechanism investigation of Lipocalin-2 in ferroptosis via the AMPK/SIRT3/FOXO3a axis in sepsis-associated acute kidney injury.

Sepsis-associated acute kidney injury (SA-AKI) is a common and severe complication of sepsis. Lipocalin-2 (LCN2), a biomarker for SA-AKI, has an undefined role and underlying molecular mechanism in regulating renal ferroptosis. This study aimed to elucidate the regulatory function and potential mechanism of LCN2 in renal ferroptosis during SA-AKI. In vivo, a murine sepsis model was established using cecal ligation and puncture (CLP), while in vitro, human renal tubular epithelial cells (HK-2) were stimulated with lipopolysaccharide (LPS) to mimic SA-AKI. Histopathological, biochemical, and molecular analyses were performed to assess renal injury, oxidative stress, inflammatory responses, and ferroptosis-related indicators. In vivo, LCN2 knockout significantly attenuated renal pathological damage, reduced oxidative stress and inflammatory cytokine expression, and inhibited renal ferroptosis. Mechanistically, LCN2 knockout enhanced AMPK phosphorylation and upregulated SIRT3 expression, promoted deacetylation of FOXO3a, and upregulated the expression of antioxidant and anti-ferroptotic proteins. In vitro, LCN2 overexpression exacerbated LPS-induced ferroptosis in HK-2 cells, whereas activation of AMPK or overexpression of SIRT3 reversed this effect, as reflected by improved markers of ferroptosis and oxidative stress. Collectively, our findings suggest that LCN2 may promote renal ferroptosis and contribute to the progression of SA-AKI, potentially involving inhibition of the AMPK/SIRT3/FOXO3a pathway. These observations indicate that LCN2 could be further explored as a candidate molecular target for the clinical treatment of SA-AKI.

factors Nrf2 and NF-κ B contribute to inflammation and apoptosis induced by intestinal ischemia-reperfusion in mice

Desaminotyrosine Alleviates Hepatic Ischemia-Reperfusion Injury via the MAPK/Ferroptosis Axis and Bifidobacterium pseudolongum Modulation.

Ischemia-reperfusion (I/R) is a common and unavoidable phenomenon during surgeries such as hepatectomy and liver transplantation, severely affecting patient prognosis. However, clinically intervention and treatment measures remain very limited. Using human hepatocyte organoid hypoxia-reoxygenation (H/R) and murine hepatic ischemia-reperfusion (I/R) models, we demonstrate that the microbiota-derived flavonoid desaminotyrosine (DAT) attenuates I/R-induced hepatic injury by suppressing inflammation and apoptosis while promoting the abundance of probiotic Bifidobacterium in the gut. Through integrated spatial transcriptomics and metabolomics, we identified that DAT specifically alters the MAPK signaling pathway/ ferroptosis gene transcriptome in the portal vein (PV) zones, promotes the production of antioxidants (taurine) in the central vein (CV) zones, reduces the level of pro-ferritinosis substrates (arachidonic acid), thereby enhancing the expression of GPX4 and Nrf2, inhibiting ferroptosis, then ameliorate hepatic I/R injury. Meanwhile, the pseudo-germ-free mouse model confirmed that DAT alleviated hepatic I/R injury in a gut microbiota dependent manner. DAT reduces hepatic I/R injury by increasing the abundance of gut Bifidobacterium pseudolongum (Bif). Our research results reveal a novel microbial metabolite that improves hepatic I/R injury, clarify the inhibitory effect of DAT on ferroptosis, discover new therapeutic uses of DAT, and identify Bif as a potential novel probiotic for preventing liver I/R injury, providing new options for the preventive treatment of liver I/R injury.