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Introduction The activation of Transforming Growth Factor Beta (TGF-β) signalling pathway and downregulation of the cell membrane protein Caveolin-1 (CAV1) are known drivers of fibroblast activation in Systemic sclerosis (SSc). We recently reported that reduction in primary cilium (PC) length promotes fibroblast activation. The PC is a flagella-like organelle that forms a signalling hub for pathways involved in cellular homeostasis, some of them found dysregulated in SSc.Material and Methods Dermal fibroblasts from healthy control (HC), VEDOSS and SSc patients were isolated and immortalized using human telomerase reverse transcriptase. PC stained with acetylated-a-tubulin for confocal microscopy. Cells were treated with TGF-β(10 ng/mL) and inhibitors of TGFβR1 (SD208, 1 μM), ROCK2 (KD025, 5 μM),HDAC (Tubacin, 10 μM),and Aurora A kinase (AURKA) (MLN8054, 10 μM). CAV1 knockdown in HC fibroblasts was performed using lenti-shCAV1. Gel contraction assay was used to analyse fibroblast activity in vitro.Results Primary or immortalised VEDOSS and SSc dermal fibroblasts had shorter PC than HC cells (2.5±0.1 μm vs 2.8±0.1 μm vs 4.4±0.2 μm ; p< 0.0001), a stable phenotype insensitive to TGFβR1 inhibition. TGFβ treatment significantly reduced PC length of both HC (4.2±0.1 μm to 1.6±0.02 μm)and SSc (2.6±0.07 μm to 1.6±0.1 μm) cells. However, PC shortening by TGFβ was reversed upon TGFβ withdrawal, prevented by SD208 and partially sensitive to ROCK2 inhibition. In contrast, inhibition of HDAC6, a known negative regulator of cilium length, significantly increased SSc PC length (2.6±0.1 μm to 3.3±0.03 μm; p<0.01). Inhibition of AURKA, an upstream regulator of HDAC6, significantly increased SSc PC length to HC levels (2.8±0.2 μm to 3.9±0.3 μm; p<0.01), and reduced SSc fibroblasts contractility of a collagen matrix over 48h (78% to 87% gel contraction from 0h; p<0.02). Finally, knockdown of CAV1 reduced HC fibroblast PC to a similar length to SSc fibroblasts and increased gel contraction, which were also rescued by AURKA inhibition.Conclusions All together we confirmed that PC length is stably reduced in SSc and VEDOSS dermal fibroblasts by a CAV1-AURKA-HDAC6 mechanism independently of TGFβ signalling. TGFβ activation can rapidly and reversibly shorten PC length, as previously reported, by a pathway partially dependent on ROCK2. Moreover, we demonstrated that inhibition of the AURKA-HDAC6 axis was able to increase PC length in SSc and shCAV1 fibroblasts to HC levels and reduced their contractile capacity. These findings highlight the potential significance of CAV1 and AURKA-HDAC6 as contributors to profibrotic activation and identify potential therapeutic targets for tissue fibrosis.