Experimental eye research · 2026
Knocking down FSTL1 reduces TGF-β2-induced trabecular meshwork fibrosis and ocular hypertension via inhibition of the Smad3 signaling pathway.
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Wen Lixin, Yang Yunlin, Gao Yaohua, Hou Mingmin, Sun Hao, Guo Tao
Аннотация
BACKGROUND: Excessive accumulation of extracellular matrix (ECM) in the trabecular meshwork (TM) increases aqueous humor outflow resistance, leading to elevated intraocular pressure (IOP) and the development of primary open-angle glaucoma (POAG). Transforming growth factor-β2 (TGF-β2) is a well-established profibrotic mediator implicated in TM fibrosis. Despite its recognized role in promoting ECM deposition, the downstream regulatory mechanisms remain incompletely understood. Follistatin-like 1 (FSTL1), a secreted glycoprotein involved in various fibrotic diseases, has recently drawn attention, yet its role in TM fibrosis and IOP regulation in POAG remains unclear.
METHODS: TGF-β2-induced human trabecular meshwork (HTM) cells and a murine model of TGF-β2-induced ocular hypertension were employed. Proteomic analysis, Western blotting, quantitative real-time PCR, and immunofluorescence were used to assess ECM expression and TGF-β2/Smad3 signaling. Loss-of-function approaches were applied to examine the role of FSTL1 in trabecular meshwork fibrosis and intraocular pressure regulation.
RESULTS: FSTL1 was induced by TGF-β2 and associated with enhanced ECM accumulation and Smad3 activation in HTM cells. Silencing FSTL1 reduced TGF-β2 induced ECM deposition and p-Smad3 accumulation in vitro, and intraocular FSTL1 knockdown mitigated TM fibrosis and lowered TGF-β2-induced ocular hypertension in mice.
CONCLUSION: These findings identify FSTL1 as an important regulator of TGF-β2-induced TM fibrosis. FSTL1 contributes to ECM accumulation and IOP elevation with Smad3 signaling under profibrotic conditions. Targeting FSTL1 may represent a potential therapeutic strategy for limiting TM fibrosis and IOP elevation in POAG.
METHODS: TGF-β2-induced human trabecular meshwork (HTM) cells and a murine model of TGF-β2-induced ocular hypertension were employed. Proteomic analysis, Western blotting, quantitative real-time PCR, and immunofluorescence were used to assess ECM expression and TGF-β2/Smad3 signaling. Loss-of-function approaches were applied to examine the role of FSTL1 in trabecular meshwork fibrosis and intraocular pressure regulation.
RESULTS: FSTL1 was induced by TGF-β2 and associated with enhanced ECM accumulation and Smad3 activation in HTM cells. Silencing FSTL1 reduced TGF-β2 induced ECM deposition and p-Smad3 accumulation in vitro, and intraocular FSTL1 knockdown mitigated TM fibrosis and lowered TGF-β2-induced ocular hypertension in mice.
CONCLUSION: These findings identify FSTL1 as an important regulator of TGF-β2-induced TM fibrosis. FSTL1 contributes to ECM accumulation and IOP elevation with Smad3 signaling under profibrotic conditions. Targeting FSTL1 may represent a potential therapeutic strategy for limiting TM fibrosis and IOP elevation in POAG.