Kazachstania pintolopesii triggers an immune-endothelial-fibroblast cascade and drives inflammatory arthritis and tissue fibrosis in genetically susceptible hosts

Emerging evidence underscores the critical role of microbiota dysbiosis in autoimmune pathogenesis, yet direct links between specific microbial species and disease mechanisms remain poorly defined. Our prior work identified <i>Kazachstania pintolopesii</i>, a gut-dwelling fungus isolated from spontaneous ankylosing spondylitis (AS)-prone monkeys, as a potent inducer of PANoptosome assembly. However, the multicellular and molecular mechanisms underlying its pathogenicity remained elusive. Here, we elucidate how lysates of <i>K. pintolopesii</i>(LKP) disrupt immune homeostasis through immune-endothelial-fibroblast crosstalk, metabolic reprogramming, and dysregulated cytokine networks in genetically susceptible hosts. Using single-nucleus RNA sequencing and functional assays, we demonstrate that LKP triggers robust inflammatory arthritis and tissue fibrosis in <i>BALB/c ZAP70W163C</i>mutant mice. Results showed that LKP injection induces severe joint destruction, spinal deformities, and upregulation of pro-inflammatory cytokines (IL-1β, IL-6, NF-κB) in joint tissues; immune-endothelial-fibroblast networks are dysregulated, with T cells promoting osteoclastogenesis via ligand-receptor interactions (e.g., <i>Sema4d-Plxnb1</i>) and endothelial cells exhibiting impaired migratory capacity and glycolytic reprogramming; fibroblast-like synoviocytes (FLS) undergo abnormal proliferation, with subpopulations (e.g., Fib_<i>Cmss1</i>, Fib_<i>Tnc</i>) driving extracellular matrix remodeling through TGF-β/PI3K-Akt signaling; and distinct macrophage subtypes (e.g., Mac_<i>Adam8</i>, Mac_<i>mt-Col</i>) exhibit ferroptosis and PI3K-Akt activation, contributing to osteoclastogenesis and cartilage degradation. Mechanistically, LKP disrupts mitochondrial function, enhances IL-17/TNF-α signaling, and induces pan-inflammatory responses in genetically predisposed hosts. Therapeutic targeting of these pathways (e.g., IL-17/IL-6 inhibitors, metabolic modulators) may disrupt the pathogenic cascade. Our findings establish <i>K. pintolopesii</i> as a keystone pathobiont in autoimmune arthritis and fibrosis, offering actionable insights for precision medicine.