Sepsis is characterized as a systemic inflammatory response syndrome (SIRS). It occurs when the body’s immune system mounts an excessive response to an infection, leading to a cytokine storm and pathological inflammation.1,2 An estimated 48.9 million cases of sepsis and 11 million related deaths occur annually worldwide.3 Sepsis patients who survive often develop long-term health problems, including organ dysfunction, which increases the consumption of social medical resources. Acute kidney injury (AKI) is one of the most prevalent complications during the early stages of sepsis and represents a leading cause of mortality in intensive care units (ICUs).4 Recent research indicates that sepsis is a common cause of AKI in hospitalized patients. The prevalence of septic shock in sepsis-associated AKI (SA-AKI) patients is 60.47 %.5 Among ICU patients, sepsis accounts for over half of all AKI cases.6 Following the onset of sepsis, it aggravates kidney damage, impairs renal function recovery, and complicates pharmacological treatment.

Upon the onset of sepsis, multiple immune cells engage in a complex immune network response, releasing substantial quantities of endogenous inflammatory mediators.7 These mediators play a pivotal role in the pathogenesis of AKI by creating an inflammatory microenvironment characterized by immune cell infiltration into renal tubules. This triggers a cascade of cellular responses, including autophagy, mitochondrial dysfunction, loss of cellular polarity, apoptosis, and ferroptosis.8 Collectively, these processes lead to compromised renal tubular function.

Ferroptosis, a non-apoptotic form of cell death, is particularly notable as it involves iron-dependent regulated necrosis caused by extensive lipid peroxidation and subsequent membrane damage, driven by dysregulated intracellular iron levels.9 Numerous studies have demonstrated a strong association between ferroptosis and organ damage in the lungs, liver, and other tissues.10,11 Research has shown that GPX4 expression is significantly downregulated in ischemia-reperfusion-induced acute kidney injury (AKI). Additionally, knockdown of Tripartite Motif Containing 21 (TRIM21), an upstream E3 ubiquitin ligase responsible for GPX4 degradation, effectively upregulates GPX4 expression and mitigates ferroptosis in AKI.12 The NRF2 antioxidative pathway also plays a critical role in AKI pathogenesis. It counteracts ferroptosis-related changes by modulating key biochemical indicators such as malondialdehyde (MDA) levels, superoxide dismutase (SOD) activity, and glutathione (GSH) depletion in cisplatin-induced AKI.13 These findings suggest that ferroptosis may significantly contribute to sepsis-associated renal disease by promoting tubular epithelial cell injury.

The AhR, a ligand-dependent transcription factor, is widely expressed in barrier tissues, including immune cells, epithelial cells, and endothelial cells. Under normal conditions, AhR resides in the cytoplasm as a complex with chaperone proteins. Upon ligand binding, AhR translocates to the nucleus through the nuclear pore complex, where it activates the transcription of target genes.14 Previous studies have revealed a strong link between the AhR signaling pathway and lipid peroxidation. In renal diseases, AhR activation alleviates acute kidney injury by suppressing inflammatory responses and apoptosis.15 Furthermore, AhR regulates NRF2 and its downstream genes in membranous nephropathy. However, the precise mechanisms underlying AhR’s role in sepsis-induced acute kidney injury remain unclear. This study aims to elucidate the protective mechanisms of AhR in sepsis-associated AKI