Metabolic dysfunction-associated steatotic liver disease: Mechanisms, metabolic reprogramming, and therapeutic insights

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive metabolic disorder that is pathologically characterized by abnormal lipid deposition in the liver and metabolic inflammation. The current clinical management of MASLD largely involves generalized lifestyle modifications including diet and broad-spectrum metabolic interventions such as insulin sensitizers. These approaches often yield suboptimal outcomes because of poor long-term adherence, heterogeneous patient responses, and limited efficacy in advanced disease stages. Crucially, they fail to address disease-specific molecular drivers, such as aging-associated pathways exemplified by vitamin D receptor dysregulation. Given the complexity and progressive nature of MASLD, it is crucial to further elucidate its mechanisms, develop precise therapeutic strategies, and raise awareness of the disease among the public and medical community.

Keywords: Metabolic dysfunction-associated steatotic liver disease; Aging; Vitamin D receptor; Metabolic reprogramming; Ferroptosis

Core Tip: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive disorder intricately linked to aging through shared pathological pathways. The core mechanism driving aging-aggravated MASLD involves vitamin D receptor (VDR) dysregulation, which amplifies hepatic lipotoxicity by disrupting lipid metabolism and inducing ferroptosis. Although metabolic reprogramming initially serves as an adaptive response to stress, its dysregulation in aging accelerates inflammation and fibrosis. However, precisely targeting the VDR–p53 axis to modulate mitochondrial function and ferroptotic susceptibility, while balancing metabolic adaptation and cell death, remains a critical therapeutic challenge for halting disease progression.