Lentinan attenuates histone deacetylation of SOCS1 promoter to remodel autophagy via JAK2/STAT3 pathway for the prevention of intervertebral disc degeneration.

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Citation abstract

Intervertebral disc degeneration (IVDD), driven by nucleus pulposus cell (NPCs) apoptosis, extracellular matrix (ECM) dyshomeostasis, and inflammation, lacks effective therapies. Lentinan (LNT), a polysaccharide from lentinula edodes, has anti-inflammatory and antioxidant properties. However, the role and molecular mechanisms of LNT in IVDD are unclear. In vitro, LNT counteracted IL-1β-induced NPCs apoptosis by restoring mitochondrial function, suppressing reactive oxygen species (ROS) accumulation, and rebalancing ECM metabolism via regulation of anabolic and catabolic markers. Mechanistic studies revealed that LNT enhanced autophagic flux by upregulating Suppressor of Cytokine Signaling 1 (SOCS1) expression, which inhibited Janus Kinase2 (JAK2) / Signal Transducer and Activator of Transcription 3 (STAT3) hyperactivation, thereby alleviating NPCs senescence and apoptosis under inflammation. Specifically, LNT downregulates histone deacetylase 6 (HDAC6), enhancing histone H3 lysine 27 acetylation (H3K27ac). This epigenetic modification promotes SOCS1 enhanced expression, which in turn suppresses the JAK2/STAT3 pathway, ultimately alleviating intervertebral disc degeneration. In vivo, LNT administration in a rat caudal IVDD model attenuated disc degeneration, as evidenced by preserved disc morphology, reduced ECM degradation. Immunohistochemical (IHC) and immunofluorescence (IF) experiments demonstrated that lentinan mediates the regulation of SOCS1 and restores the impaired autophagy status in rat tail intervertebral discs following puncture-induced injury. In human nucleus pulposus specimens, we have also identified the involvement of SOCS1/JAK2/STAT3 signaling in aged and degenerated nucleus pulposus. Consequently, LNT may be a promising candidate for the treatment of IVDD.