2. Academic Validation
  3. Methyl 3,4-dihydrobenzoate attenuates muscle fiber necroptosis and macrophage pyroptosis by regulating oxidative stress in inflammatory myopathies

Methyl 3,4-dihydrobenzoate attenuates muscle fiber necroptosis and macrophage pyroptosis by regulating oxidative stress in inflammatory myopathies

  • Int Immunopharmacol. 2025 May 8:154:114608. doi: 10.1016/j.intimp.2025.114608.
Qiwen Tang 1,  Jiao Cheng 2,  Tao Zhu 3,  Zhijie Zhou 4,  Ping Xia 5
Affiliations

Affiliations

  • 1 Department of Neurology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3 East Qingchun Road, Hangzhou 310016, China.
  • 2 Department of Orthopaedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China; Key Laboratory of Mechanism Research and Precision Repair of Orthopaedic Trauma and Aging Diseases of Zhejiang Province, Hangzhou 310016, China.
  • 3 Department of Pathology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3 East Qingchun Road, Hangzhou 310016, China.
  • 4 Department of Orthopaedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China. Electronic address: zhouzj78@zju.edu.cn.
  • 5 Department of Neurology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3 East Qingchun Road, Hangzhou 310016, China. Electronic address: 3408043@zju.edu.cn.
PMID: 40186902 DOI: 10.1016/j.intimp.2025.114608
Abstract

Inflammatory cell infiltration and myofiber necrosis are pathological hallmarks of idiopathic inflammatory myopathies (IIM). Methyl 3,4-dihydroxybenzoate (MDHB) is a natural phenolic acid compound, renowned for its anti-inflammatory and antioxidant effects. In this study, we investigated its protective mechanisms targeting muscle fiber necrosis and macrophage Pyroptosis by regulating oxidative stress in IIM. In the present study, we found that increased Reactive Oxygen Species (ROS) level and decreased nuclear factor erythroid 2 related factor 2 (Nrf2) protein expression were shown on the muscle fibers of experimental autoimmune myositis (EAM). Receptor-interacting protein 1 (RIPK1) and receptor-interacting protein 3 (RIPK3) protein expression were elevated in EAM. In vitro, MDHB protected C2C12 cells and myotubes against H2O2-induced cell viability damage. MDHB decreased the levels of oxidative stress such as ROS, and mitochondrial superoxide (MitoSOX), and rescued mitochondrial membrane potential and ATP generation. MDHB inhibited Necroptosis of the C2C12 cells and myotubes under H2O2 stimulation in a dose-dependent manner. Furthermore, MDHB suppressed lipopolysaccharide and nigericin-induced Caspase-1 cleavage and interleukin (IL-1β) secretion, indicating suppression of macrophage Pyroptosis in vitro. In vivo, treatment with MDHB suppressed EAM-induced muscle weakness and inflammation. MDHB decreased ROS accumulation, and increased Nrf2 and heme oxygenase-1 (HO-1) expression in EAM mice's muscles, thereby inhibiting Necroptosis of inflamed muscle species and macrophage Pyroptosis. In conclusion, we demonstrated that MDHB could be a novel therapy for IIM that alleviates inflammation, muscle fiber Necroptosis, and macrophage Pyroptosis by regulating the Nrf2/HO-1 pathway.

Keywords

Inflammatory myopathies; Methyl 3,4-dihydrobenzoate; Necroptosis; Oxidative stress; Pyroptosis.

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