Background/Purpose: Systemic sclerosis (SSc) is a life-threatening autoimmune disease where fibroblasts (FB) contribute to disease severity by resisting apoptosis and driving excessive skin fibrosis. Among the limited treatment options, autologous stem cell transplantation (ASCT) is the only disease-modifying therapy, but its effects on restoring FB function remain unknown. We recently identified polysialic acid (polySia), a cancer-associated glycan, in skin sections from patients with SSc; polySia levels correlate with fibrosis and normalize post-ASCT. Additionally, severe-SSc skin has genomic instability associated with double-stranded-DNA-breaks (DSBs), which activate a transcription factor, FOXO1, to prolong FB survival. We hypothesized that the FOXO1 pathway might drive polySia expression, thereby contributing to increased cell survival and fibrosis.

Methods: We generated primary dermal fibroblast from skin biopsies of healthy controls (HC), less severe SSc (lSSc), severe fibrotic diffuse SSc (dSSc), and post-ASCT patients. DSB frequency, active (nuclear) FOXO1, and polySia levels were assessed using immunofluorescence/confocal microscopy and immunoblotting. Following FOXO1 pharmacological inhibition, we quantified polySia synthetic enzymes (ST8Sia2/4) and pro-fibrotic markers using qRT-PCR. Resistance-to-apoptosis was evaluated via TUNEL assay following inhibiting FOXO1 activity and polySia synthesis.

Results: In dSSc FB, DSBs, FOXO1 and polySia expression (ST8Sia2/4) were highest compared to lSSc and HC. Importantly, post-ASCT FB had decreased levels of these compared to dSSc. FOXO1 inhibition in dSSC resulted in increased resistance-to-apoptosis, decreased fibrotic-markers (e.g. fibronectin, CTGF) and ST8sia2/4 levels. Also, pharmacological inhibition of polySia synthesis increased resistance-to-apoptosis in dSSc FB. Suggesting that the FOXO1/polySia axis is critical for ASCT’s beneficial effects in dSSc.

Conclusion: Our study identifies a novel DSB/FOXO1/polySia pathway as a key driver of severe SSc. This axis may serve as a biomarker for SSc disease progression and treatment response while providing insight into how ASCT restores fibroblast function. Targeting the FOXO1/polySia pathway could offer therapeutic potential for SSc and other fibrotic diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/foxo1-mediated-polysialic-acid-dysregulation-in-severe-systemic-sclerosis-ssc-a-novel-biomarker-and-therapeutic-target/