AAV induces hepatic necroptosis and carcinoma in diabetic and obese mice dependent on Pebp1 pathway

Abstract

Obesity and diabetes are risk factors for hepatocellular carcinoma (HCC); however, the underlying mechanisms are yet to be elucidated. Adeno‐associated virus (AAV) frequently infects humans and has been widely used in gene therapy, but the risk of AAV infection such as HCC should be further evaluated. Here, we show that recombinant AAV injection caused liver injury, hepatic necroptosis, and HCC in db/db or high‐fat diet‐induced hyperglycemic and obese mice, but not in mice with only hyperglycemia or obesity. Prednisone administration or knockdown of Pebp1, highly expressed in db/db mice, alleviated hepatic injury and necroptosis induced by recombinant AAV in mice with diabetes and obesity. Inhibition of Pebp1 pathway also attenuated inflammation and necroptosis in vitro . Our findings show that AAV infection is a critical risk factor for HCC in patients with diabetes and obesity, and AAV gene therapy for these patients should be carefully evaluated. Both prednisone treatment and targeting Pebp1 pathway are promising strategies to alleviate inflammation and necroptosis that occurred in AAV gene therapy or related diseases. image Hepatic necroptosis and HCC were caused by recombinant AAV injection in hyperglycemic and obese mice, which could be alleviated by prednisone administration or Pebp1/Tbk1 signaling inhibition. Injection of rAAV induced hepatic necroptosis and carcinoma in hyperglycemic and obese mice, but not in hyperglycemic and slim mice or euglycemic and obese mice. Oral administration of prednisone significantly alleviated rAAV‐induced hepatic necroptosis in hyperglycemic and obese mice. Pebp1/Tbk1 mediated rAAV‐induced hepatic necroptosis in hyperglycemic and obese mice.