Sculpting liver-related injury in type 2 diabetes mellitus: Decoding serum ferritin's correlation and ferroptosis pathways

We aimed to assess whether serum ferritin levels are a risk factor for hepatic-related injury in patients with type 2 diabetes mellitus (T2DM) and investigate the role of ferroptosis in this pathological process. A retrospective cohort study and Mendelian randomization analysis were conducted to investigate the association between serum ferritin levels and liver-related outcomes. Furthermore, dB/dB mice and the GSE230674 dataset were used to analyze liver iron metabolism-related indicators and the ferroptosis pathway. Findings from this retrospective cohort study revealed that an elevated serum ferritin level is a relatively independent risk factor for liver-related injuries in patients with T2DM, including nonalcoholic fatty liver disease, hepatocellular injury, and cholestasis. Subgroup analysis suggested that this relationship was absent in patients with anemia. Mendelian randomization analysis indicated a causal relationship between increased hepatic iron storage and disruptions in iron metabolism, leading to elevated alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and direct bilirubin levels. Furthermore, diabetic mice with concomitant nonalcoholic fatty liver disease exhibited hepatic iron overload and activation of ferroptosis pathways. After intervention with ferrostatin-1, there was a reduction in liver injury-related biomarkers and suppression of ferroptosis. Serum ferritin is a risk factor for liver-related injuries in patients with T2DM with normal hemoglobin levels. In this context, activation of the ferroptosis pathway due to hepatic iron overload may play a crucial role. In addition, treatment strategies focused on inhibiting the hepatic ferroptosis pathway are promising.