Asian Journal of Pharmaceutical Sciences · Nov 2026
Oral Polyprodrug Reprograms the Hepatic Metabolism–Aging Axis for Systemic Anti-Aging
By Zhang W, Sha Y, Luo Y et al.
Obesity, aging and metabolic disorders are intricately interconnected, with each condition exacerbating the others and creating a self-reinforcing pathological cycle. As the central organ governing systemic metabolism, the liver plays a pivotal role in coordinating energy homeostasis, inflammation, and pathways related to aging. We hypothesized that disrupting this cycle specifically within the liver could offer a targeted and effective strategy for treating obesity and aging-related metabolic dysfunctions. To this end, we developed a novel polyprodrug platform, poly(ursodeoxycholic acid–butyrate) (PUDCA-But), synthesized by covalently conjugating ursodeoxycholic acid (UDCA) and butyrate into a polymeric backbone. This design simultaneously integrates the metabolic and anti-inflammatory benefits of both components. PUDCA-But enables multipathway regulation across metabolic, inflammatory, and senescence-related networks. Notably, it significantly upregulates the expression of the “longevity factor” fibroblast growth factor 21 (FGF21) via multiple signaling pathways. In both in vitro and in vivo studies, PUDCA-But exhibited superior therapeutic efficacy compared to its individual components, improving liver function and alleviating hepatic steatosis, fibrosis, inflammation, and cellular senescence in diet-induced obese mice. Importantly, this study introduces an innovative therapeutic paradigm that targets and disrupts the hepatic metabolism–aging axis to restore systemic metabolic and aging homeostasis. By integrating this concept with a rationally designed oral polyprodrug platform, we offer a new strategy for the treatment of age-related metabolic disorders.