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

Obesity and diabetes are risk factors for hepatocellular carcinoma (HCC), while the underlying mechanisms are yet to be elucidated. Adeno-associated virus (AAV) frequently infected in humans has been widely used in gene therapy, but the risk of AAV infection such as HCC should be further evaluated. Here we show 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 only with 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 can also attenuate 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 occurred in AAV gene therapy or related diseases.