Osteoarthritis (OA), the most common joint disease, is characterized by inflammation and cartilage degradation. Previous studies illustrated that Smad nuclear-interacting protein 1 (SNIP1) is an inhibitor of the TGF-β signal transduction pathway and SNIP1 has been reported as an anti-inflammatory factor. This study aimed to explore the role of SNIP1 in OA progression. In this study, the SNIP1 expression was evaluated in OA human and OA mice tissue and interleukin-1 beta (IL-1β)-induced chondrocytes . The Safranin-O (SO) staining and osteoarthritis research society international (OARSI) scoring system was used to evaluate cartilage injury. The gain- and loss-of-function studies for SNIP1 were performed in chondrocytes. The SNIP1 overexpression adenovirus was injected into mice by intra-articular injection. The SNIP1 expression was decreased in OA patients, OA mice, and IL-1β-stimulated chondrocytes. The cartilage injury of medial meniscus-induced OA (DMM-OA) mice at 8 weeks showed more severe than that at 4 weeks. The expression of SNIP1 was lower at 8 weeks than that at 4 weeks. In IL-1β-stimulated chondrocytes, SNIP1 overexpression reduced the expression of TNF-α and IL-6, alleviated ECM degradation, reduced the phosphorylation levels of p65 and IκBα , and decreased the p65 level in nuclear. Moreover, overexpression of SNIP1 alleviated cartilage injury in DMM-OA mice. In brief, our study suggested that SNIP1 alleviated OA and repressed inflammation by inhibiting the activation of NF-κB. This study might provide a new insight into OA treatment.
The physical interfaces governing macromolecular protein–protein interactions dictate critical gene transcription programs, yet the structural basis of regulatory complexes inhibiting NF-κB remains partially resolved. Here, we characterize the macromolecular interaction between Smad nuclear interacting protein 1 (SNIP1) and the transcriptionally active p65 subunit of NF-κB, a regulatory axis whose pathological downregulation was identified via comparative proteomics of human osteoarthritic cartilage. GSE114007 and descriptive single-cell analyses of GSE152805 showed lower SNIP1 expression in diseased cartilage; GSE169077 showed the same direction without statistical significance. Co-immunoprecipitation confirmed the endogenous physical association of SNIP1 and p65 in human chondrocytes. Molecular docking and molecular dynamics (MD) simulations mapped a candidate SNIP1–p65 interface with a negative MM/GBSA endpoint estimate (ΔGbind = −209.6 kJ/mol, 95% CI −381.4 to −37.8 kJ/mol across three trajectory means). The computational models position SNIP1 Arg-287 and Arg-288 within a cationic interface that is sterically incompatible with the DNA-bound conformation of p65. Computational substitution analysis further identified Arg-288 as a candidate hotspot residue, with charge-reversal substitutions predicted to destabilize the complex; this residue-level prediction awaits experimental site-directed mutagenesis. An assumption-based ODE model illustrates the sensitivity of downstream outputs to imposed SNIP1-dependent inhibition without establishing clinical kinetics or residue-specific causality. Overall, the combined data define a testable structural model for SNIP1-mediated regulation of p65 while avoiding causal attribution to Arg-288 before experimental validation.
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