Insulin-Like Growth Factor-Binding Protein 7 and Cadmium-Induced Hepatorenal Fibrosis

Background: Chronic cadmium exposure can induce the onset and progression of hepatorenal fibrosis; however, its molecular basis is unclear. Insulin-like growth factor-binding protein 7 (IGFBP7) is not only a biomarker of acute kidney injury (AKI), but also plays a functional role in promoting kidney injury and inflammation. Abnormal repair of AKI causes kidney fibrosis and chronic kidney disease. IGFBP7 has also been reported as a more sensitive biomarker for liver fibrosis. However, its role in hepatorenal fibrosis requires further investigation. Methods: IGFBP7 global and conditional knockout mice were used to determine the role of IGFBP7 in cadmium-induced hepatorenal fibrosis. Then, liquid chromatography-mass spectrometry, truncated mutants, co-immunoprecipitation, and microscale thermophoresis were employed to unravel the downstream mechanisms. Results: IGFBP7 expression was significantly elevated in kidney and liver tissues of mice subjected to chronic cadmium exposure. IGFBP7 deficiency attenuated cadmium-induced hepatorenal dysfunction and fibrosis, whereas restoration of IGFBP7 expression in IGFBP7-deficient mice reproduced hepatorenal fibrosis. Mechanistically, IGFBP7 interacted with alpha-enolase (ENO1) and inhibited its ubiquitination and degradation. Upregulated ENO1 further promoted glucose metabolic reprogramming and lactate accumulation. Conversely, lactate accumulation enhanced IGFBP7 transcription and expression through histone H3K18 lactylation. Importantly, therapy targeting IGFBP7 significantly ameliorated cadmium-induced hepatorenal fibrosis. Conclusions: IGFBP7 promoted cadmium-induced hepatorenal fibrosis by enhancing ENO1-driven abnormal glycolysis and lactate accumulation.