Oleanolic acid (OA) has anti-hepatocellular carcinoma (HCC) effects, but the underlying mechanisms remain incompletely understood. Ferroptosis, a type of regulated cell death that depends on iron, offers a hopeful therapeutic target in HCC. In this study, we identify a heretofore unrecognized mechanism by which OA, a natural pentacyclic triterpenoid, exerts potent anti-HCC activity through the induction of STING-dependent ferroptosis. We herein provide the first evidence that OA-induced mitochondrial damage leads to the efflux of mtDNA into the cytosol. Once released, this mtDNA functions as an endogenous danger-associated molecular pattern to activate STING signaling, which in turn precipitates a cascade of ferroptotic events-including lipid peroxidation, ferrous iron accumulation, and GSH depletion-observed consistently across in vitro and in vivo settings. Crucially, STING knockdown significantly attenuates OA-induced ferroptosis and abrogates its antitumor efficacy, establishing STING as a functional mediator of OA activity. Moreover, we provide the evidence that OA binds to STING protein, enhancing its protein stability by suppressing ubiquitin-proteasome-mediated degradation. Collectively, our findings uncover a dual mechanism of action for OA: it acts as an upstream trigger of mtDNA-driven STING activation and as a pharmacological stabilizer of STING. This study not only reveals a novel mechanistic link between mtDNA/STING signaling and ferroptosis in HCC but also identifies STING as a previously unrecognized target of OA, positioning OA as a promising lead compound for HCC therapy.
Methylmercury chloride (CH₃HgCl)-induced neurotoxicity is associated with oxidative stress, neuroinflammation, glutamate dysregulation, apoptosis, and progressive neuronal injury. Chitinase-3-like protein 1 (CHI3L1) plays an important role in neuroinflammatory processes and represents a potential therapeutic target in neurodegenerative disorders. Kasugamycin is an aminoglycoside antibiotic primarily used in agriculture as a bactericide and fungicide. Beyond its agricultural applications, kasugamycin exhibits anti-inflammatory and immunomodulatory properties; however, its potential therapeutic application in neurological disorders is limited by poor brain penetration and limited pharmacokinetic characteristics. Therefore, this study aimed to investigate the neuroprotective potential of liposomal kasugamycin against CH₃HgCl-induced neurotoxicity in rats. Kasugamycin-loaded liposomes were prepared using the thin-film hydration technique and optimized through a Central Composite Design approach. The optimized formulation was characterized for physicochemical properties and in vitro drug release before evaluation in a rat model of CH₃HgCl-induced neurotoxicity. Neuroprotective efficacy was assessed using behavioral, biochemical, molecular, and histopathological parameters. The optimized formulation exhibited nanoscale particle size and high encapsulation efficiency. Liposomal kasugamycin significantly improved locomotor performance and body weight while attenuating oxidative stress, neuroinflammation, apoptosis-related alterations, glutamate dysregulation, and neuronal injury. Treatment restored superoxide dismutase (SOD) and reduced glutathione (GSH) levels while decreasing malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), Bax, caspase-3, and glutamate levels. Furthermore, liposomal kasugamycin increased Bcl-2 and myelin basic protein (MBP) expression and modulated CHI3L1 expression, suggesting potential involvement of neuroinflammatory and neuroprotective pathways. To the best of our knowledge, this study provides the first evidence of the neuroprotective potential of liposomal kasugamycin against CH₃HgCl-induced neurotoxicity, supporting further investigation of this formulation as a potential therapeutic strategy for mercury-associated neuronal injury.
