YAP1 protects against septic liver injury via ferroptosis resistance

The liver plays crucial roles in sepsis and is one of the major targets for sepsis-related injuries. Ferroptosis, a newly emerged form of lytic cell death, has been implicated in sepsis related organ failure. Yes-associated protein1 (YAP1), a key regulator of the Hippo signaling pathway, may be involved in ferroptosis development. This study aimed to elucidate the role of YAP1 in septic liver injury through regulating ferroptosis, especially ferritinophagy-mediated ferroptosis.

Cecal ligation and puncture (CLP) models were constructed in control (Yap1^flfl) and liver-conditional knockout mice (Yap1^fl/fl Alb-Cre) to induce septic liver injury, while LO2 cells with or without YAP1 overexpression/deletion were stimulated by lipopolysaccharide (LPS) in vitro. Our study showed YAP1 knockdown aggravated CLP-induced liver injury and inflammation, as well as accelerated hepatocyte ferroptosis, revealed by down-regulated expression of GPX4, FTH1 and SLC7A11, along with up-regulated expression of SFXN1 and NCOA4. Consistently, YAP1 deficiency aggravated LO2 cells ferroptosis, but YAP1 overexpression alleviated LPS-induced LO2 ferritinophagy, as evidenced by reduced mitochondrial ROS and Fe²⁺, along with down-regulated expression of SFXN1 and NCOA4. Further co-IP assay verified that YAP1 disrupted the interaction between NCOA4 and FTH1, thus prevent the degradation of ferritin to Fe²⁺, further reduced the ROS production and suppressed ferroptosis.

YAP1 inhibits ferritinophagy-mediated ferroptosis in hepatocytes, and YAP1 deficiency aggravates sepsis-induced liver injury.