Aging aggravates acetaminophen-induced acute liver injury and inflammation through inordinate C/EBPα-BMP9 crosstalk

BACKGROUND: Previous studies have shown that bone morphogenetic protein 9 (BMP9) is almost exclusively produced in the liver and reaches tissues throughout the body as a secreted protein. However, the mechanism of BMP9 action and its role in aging-associated liver injury and inflammation are still unclear. RESULTS: Aging significantly aggravates acetaminophen (APAP)-induced acute liver injury (ALI). Increased expression of CCAAT/enhancer binding protein α (C/EBPα) and BMP9 was identified in aged livers and in hepatocytes and macrophages (MФs) isolated from aged mice. Further analysis revealed that excess BMP9 was directly related to APAP-induced hepatocyte injury and death, as evidenced by activated drosophila mothers against decapentaplegic protein 1/5/9 (SMAD1/5/9) signaling, an increased dead cell/total cell ratio, decreased levels of ATG3 and ATG7, blocked autophagy, increased senescence‐associated beta‐galactosidase (SA‐β‐Gal) activity, and a higher rate of senescence‐associated secretory phenotype (SASP) acquisition. In contrast, Bmp9 knockout (Bmp9(−/−)) partially alleviated the aforementioned manifestations of BMP9 overexpression. Moreover, BMP9 expression was found to be regulated by C/EBPα in vitro and in vivo. Notably, BMP9 also downregulated autophagy through its effect on autophagy-related genes (ATG3 and ATG7) in MΦs, which was associated with aggravated liver injury and SASP acquisition. CONCLUSIONS: In summary, the present study highlights the crucial roles played by C/EBPα-BMP9 crosstalk and provides insights into the interrelationship between hepatocytes and MΦs during acute liver injury. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-023-01014-6.