NLRP3 agonist(Kelun-Biotech)

Sepsis-induced muscle atrophy significantly impairs patient quality of life, yet effective therapeutic strategies remain limited. This study aimed to investigate the protective effects of selenomethionine (Se-Met) on sepsis-induced skeletal muscle atrophy and explore the underlying molecular mechanisms, with the goal of providing a novel theoretical foundation and potential therapeutic approach for sepsis-associated muscle injury.

A murine sepsis model was established via cecal ligation and puncture, followed by treatment with varying doses of Se-Met. Survival rate, body weight, skeletal muscle mass, and muscle strength were evaluated. Histological analysis [hematoxylin and eosin (HE) staining] was used to assess muscle fiber cross-sectional area. Protein expression levels of Atrogin-1, MuRF1, and pyroptosis-related markers (NLRP3, Caspase-1, GSDMD, IL-18, and IL-1β) were examined via Western blot. In vitro , C2C12 myoblasts were stimulated with lipopolysaccharide and treated with Se-Met to assess oxidative stress markers [reactive oxygen species (ROS), malondialdehyde, superoxide dismutase, glutathione peroxidase], pyroptosis-related proteins, and inflammatory cytokines (e.g., IL-6 and IL-18). ROS scavenger N-acetylcysteine, NLRP3 agonist, and ROS inducer were employed in mechanistic studies to further elucidate the molecular mechanisms.

Se-Met significantly improved survival, body weight, and muscle strength in septic mice and alleviated skeletal muscle atrophy. Mechanistically, Se-Met inhibited the NLRP3/Caspase-1/GSDMD signaling axis, thereby reducing pyroptosis and the expression of inflammatory cytokines such as IL-6, IL-18, and IL-1β. Furthermore, Se-Met decreased ROS accumulation, enhanced antioxidant enzyme activities, and suppressed pyroptosis through regulation of the ROS/NLRP3 pathway, ultimately reducing protein degradation mediated by Atrogin-1 and MuRF1.

This study demonstrates that Se-Met mitigates sepsis-induced skeletal muscle atrophy by exerting antioxidant effects, inhibiting pyroptosis, and modulating inflammatory responses. The findings highlight the critical role of the ROS/NLRP3 signaling pathway in the protective action of Se-Met, providing new experimental evidence for its potential application in sepsis and other oxidative stress-related diseases.

This study investigated the influence of STING on alcoholic liver disease (ALD) progression, elucidating underlying mechanism.

Mice were transfected with adenovirus-based STING shRNA and administered a diet containing 5 % alcohol. The effect of knocking down STING on ALD was determined. The NLRP3 inhibitor MCC950 was administered to ALD mice to assess the effect of NLRP3 on ALD. To investigate whether STING regulated the progression of ALD by modulating NLRP3, adenovirus-based STING shRNA transfection and NLRP3 agonist BMS-986299 treatment were performed on ALD mice. Mouse hepatocyte AML12 cells were used to elucidate the mechanism by which STING regulates the progression of ALD.

In ALD mice, knocking down STING improved liver function, relieved liver inflammation, fiber deposition, and fat accumulation, and decreased GSDMD-N/GSDMD-F, NLRP3, C-caspase1/Pro-caspase1, IL-1β, and p-p65/p65 proteins. The effects of NLRP3 deficiency on ALD mice were similar to those observed after knocking out STING. In the alcohol-induced AML12 cells and the lipopolysaccharide-adenosine triphosphate-induced pyroptosis AML12 cells, knocking down STING enhanced cell viability, attenuated apoptosis, pyroptosis, and ROS production, and decreased NLRP3, GSDMD-N/GSDMD-F, IL-1β, C-caspase1/Pro-caspase1, and p-p65/p65 protein levels. STING knockdown reduced the co-immunoprecipitation of NLRP3 protein. Treatment of ALD mice with MCC950 showed an effect similar to that observed after STING was knocked down. BMS-986299 abrogated the mitigating effect of STING knockdown on ALD mice.

Knocking down STING might block the progression of ALD by mitigating pyroptosis via downregulating NLRP3. Therefore, it might be a potential target for ALD treatment.