Urolithin A

The muscle health effects of Urolithin A are largely exerted through the following signaling pathways: Urolithin A activates AMPK through SIRT3-LKB1 axis, resulting in upregulated mitochondrial biogenesis, fatty acid oxidation, and glycogen synthesis, leading to improved energy metabolism and performance. Urolithin A also inhibits the mTOR signaling pathway by downregulating PI3K/Akt, which is important for regulating protein synthesis and cell growth. Urolithin A blocks NF-κB/STAT1 signaling by inhibiting TLR3/TRIF, which helps to reduce inflammation and promote muscle recovery. Urolithin A upregulates PGC-1α through SIRT3-LKB1-AMPK, which improves mitochondrial function and endurance. To promote protein homeostasis, Urolithin A suppresses FoxO nuclear localization and ubiquitin-proteasome degradation, and inhibits mTORC1 and the atrophy markers Atrogin-1/MuRF1.

Fig. 1 The signaling pathways and mechanisms of action of Urolithin A in muscle. (Zhao H, et al. 2023)

Synovial inflammation is one of the major factors causing OA development by inducing chronic inflammation and cartilage destruction. Targeting synovitis has been an effective approach to OA therapy, but the clinical translation of synovitis-targeting therapeutics is limited, which is ascribed to the poor targeting of drugs and the spatial heterogeneity of the joint cavity. Researchers developed pH-responsive lipid nanoparticles (LNPs@UA) loaded with Urolithin A (UA) for OA therapy. The LNPs@UA had a uniform particle size distribution, low zeta potential, and high mitochondria-targeting and pH-responsive efficiency. LNPs@UA reduced reactive oxygen species (ROS) levels, pro-inflammatory factors (IL-1β, IL-6, TNF-α) secretion, and promoted M2 macrophage polarization in vitro. Additionally, LNPs@UA could improve mitochondrial morphology, enhance autophagy and inhibit ferroptosis. In the ACLT-induced OA mouse model, LNPs@UA significantly relieved OA progression. Transcriptomic analysis suggested that NF-κB signaling was inhibited and the repair pathways were activated. These results indicated that LNPs@UA might be a potential strategy for the treatment of OA.

Fig. 2 Schematic depiction of the therapeutic strategy of LNPs@UA in combating OA. (Yi G, et al. 2025)