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The study explores how the lncRNA HOXA11-AS affects lung fibrosis through interactions with miR-148a-3p and SMAD2 in idiopathic pulmonary fibrosis.

May 16, 2026Open Access

LncRNA HOXA11-AS promotes idiopathic pulmonary fibrosis progression via sponging miR-148a-3p and regulating SMAD2

LWLidong WangJiangsu University XDXing DingJiangsu University RTRan TangJiangsu University

Key Points

The study explores how the lncRNA HOXA11-AS affects lung fibrosis through interactions with miR-148a-3p and SMAD2 in idiopathic pulmonary fibrosis.
Sixty IPF patients and 70 healthy controls were recruited.
mRNA expression was assessed using RT-qPCR and fibrosis models were established in A549 and MRC-5 cells with TGF-β1.
Functional assays included cell proliferation, apoptosis analysis, oxidative stress measurement, and dual-luciferase reporter assays.
HOXA11-AS was significantly upregulated in IPF patients and correlated negatively with lung function and the 6MWT distance (p < 0.05).
Knockdown of HOXA11-AS reduced proliferation and fibrosis markers in fibroblast cells, indicating its role in IPF progression (alike effects in A549 and MRC-5).
Inhibition of miR-148a-3p reversed the effects of HOXA11-AS knockdown on fibrosis, supporting the regulatory role of the HOXA11-AS/miR-148a-3p/SMAD2 axis.

Abstract

Abstract Background Idiopathic Pulmonary Fibrosis (IPF) is characterized primarily by progressive lung tissue scarring. This study aimed to explore the molecular mechanism of the HOXA11-AS/miR-148a-3p/SMAD2 axis in IPF. Methods Sixty IPF patients and 70 healthy controls were recruited. mRNA expression was measured by RT-qPCR. An IPF model was established in A549 cells and MRC-5 cells using transforming growth factor-beta 1 (TGF-β1) induction. Cell proliferation, apoptosis, oxidative stress levels, and fibrosis markers were assessed using the cell counting kit-8 (CCK-8), flow cytometry, and enzyme-linked immunosorbent assay (ELISA), respectively. A dual-luciferase reporter assay was conducted to confirm the regulatory interaction. Results In IPF patients, HOXA11-AS expression was significantly upregulated. Its expression was negatively correlated with lung function parameters as well as with the 6-minute walk test (6MWT) distance. Conversely, it was positively associated with fibrosis-related serum markers, such as hyaluronic acid (HA) and laminin (LN). These findings suggested that HOXA11-AS may serve as a promising diagnostic biomarker for IPF. Moreover, HOXA11-AS promoted the proliferation, suppressed apoptosis, enhanced oxidative stress by reducing superoxide dismutase (SOD) activity and increasing malondialdehyde (MDA) levels, and upregulated the key fibrosis markers expression, including alpha-smooth muscle actin (α-SMA), Collagen I, and Fibronectin. HOXA11-AS directly binds to miR-148a-3p, which in turn targets and regulates SMAD2. Notably, inhibition of miR-148a-3p reversed the suppressive effects of HOXA11-AS knockdown on TGF-β1-induced proliferation, oxidative stress, and fibrotic phenotypes in A549 cells, while restoring SMAD2 expression. Consistent results were observed in MRC-5 fibroblasts: HOXA11-AS knockdown significantly attenuated TGF-β1-induced proliferation, promoted apoptosis, and decreased the expression of α-SMA, Collagen I, and Fibronectin. These effects were partially reversed by miR-148a-3p inhibition, confirming the functional role of the HOXA11-AS/miR-148a-3p/SMAD2 axis in lung fibroblasts. Conclusions HOXA11-AS promoted the IPF progression by upregulating SMAD2 expression through the sponging of miR-148a-3p.

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