The Role of Ginsenosides in Obesity-Associated Sarcopenia: Focus on E3 Ubiquitin Ligase-Mediated Regulation of Protein Homeostasis.

Abstract

Obesity-associated sarcopenia (OAS) is a complex metabolic disorder characterized by excessive adiposity accompanied by progressive skeletal muscle loss, largely driven by impaired protein homeostasis. The ubiquitin-proteasome system (UPS) plays a central role in this process, with E3 ubiquitin ligases such as Atrogin-1, muscle ring-finger protein 1 (MuRF1), TNF receptor-associated factor 6 (TRAF6), and Parkin acting as key and non-redundant regulators of muscle protein degradation. Increasing evidence indicates that ginseng and its bioactive ginsenosides, including Rg1, Rb1, Rg3, and compound K, exert protective effects against multiple disease through modulation of E3-ligase dependent proteolytic pathways. In this review, we integrate emerging mechanistic insights into how ginseng-derived compounds orchestrate a polypharmacological regulatory network spanning inflammatory, metabolic, mitochondrial, and autophagic signaling axes. In particular, how ginsenosides target critical regulatory nodes, including TRAF6-mediated inflammatory amplification, Forkhead box O (FoxO)-driven transcription of Atrogin-1 and MuRF1, and Parkin-dependent mitochondrial quality control were summarized. Unlike single-target pharmacological agents, ginseng offers a multicomponent therapeutic strategy that simultaneously attenuates protein degradation while supporting anabolic signaling and mitochondrial adaptation. Nevertheless, significant translational challenges persist, including limited bioavailability, insufficient human skeletal muscle data, and poorly defined interactions among individual ginsenosides. Future research should prioritize standardized ginseng formulations and rigorously designed clinical trials to more clearly define its therapeutic potential in the management of OAS.