The p97-UBXN1 complex regulates aggresome formation.

Sepsis-associated acute kidney injury (SA-AKI) is a common complication in septic patients and is associated with high mortality and progression to chronic kidney disease. Previous studies have demonstrated that thymosin β4 (Tβ4) attenuates lipopolysaccharide (LPS)-induced liver injury and ischemic AKI by suppressing inflammatory responses. Here, we aimed to investigate the effects of Tβ4 on SA-AKI and elucidate its underlying mechanisms. In vivo and in vitro models of SA-AKI were established using LPS. Tβ4 was administered 30 min after LPS exposure. Transcriptome sequencing was performed to explore the underlying molecular mechanisms, followed by validation using western blotting and qRT-PCR. In SA-AKI mice, serum Tβ4 levels were significantly decreased. Administration of Tβ4 ameliorated renal dysfunction and morphological injury in LPS-treated mice, accompanied by reduced renal inflammation and apoptosis. Transcriptome-sequencing analysis indicated that the MAPK signaling pathway was involved in both SA-AKI pathogenesis and the protective effect of Tβ4. Western blotting of the renal tissues confirmed that LPS enhanced the phosphorylation of JNK1/2, p38 MAPK, and ERK1/2, while Tβ4 significantly suppressed their activation. In HK-2 cells, pharmacological activation of the MAPK pathway with anisomycin restored MAPK phosphorylation and partially reversed the inhibitory effects of Tβ4 on the mRNA expression of the pro-inflammatory cytokines IL-6, IL-1β, and IL-18. In conclusion, Tβ4 alleviates renal inflammation and apoptosis in SA-AKI by suppressing the MAPK signaling pathway. Tβ4 may represent a potential therapeutic strategy for early intervention in SA-AKI.