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Introduction Idiopathic pulmonary fibrosis (IPF) is a progressive disease with no effective treatment. The melastatin-type transient receptor potential 7(TRPM7) bifunctional protein acts as an ion channel and a kinase. It is involved in Ca 2+/Mg2+ homeostasis, cell growth and proliferation and has been linked to promoting profibrotic activity in cardiac fibroblasts, but its role in IPF and human lung myofibroblasts (HLMFs) pro-fibrotic function remains unclear. Therefore, we aim to investigate TRPM7 expression and function in HLMFs.Methods TRPM7 mRNA expression (± TGFβ1) was assessed via qRT-PCR and Affymetrix Human Gene 2.1 ST genome-wide microarray in several lung cell types. TRPM7 currents were analysed using patch-clamp electrophysiology and manipulated with Mg 2+, Naltriben and TRPM7 inhibitor, waixenicin A (500nM). TRPM7 knockdown was achieved using siRNA, and fibrotic markers (αSMA, Collagen 1, and Collagen 6) were quantified by RT-PCR. MTS assay, flow cytometry and wound healing were utilised to assess the effects of waixenicin A on HLMF viability, proliferation and migration. DNA methylation was profiled with Illumina Infinium MethylationEPIC BeadChip.Results TRPM7 is highly expressed in airway fibroblasts compared to airway epithelial cells (p<0.0001). However, in disease TRPM7 is significantly downregulated, IPF HLMF(p<0.05), IPF airway fibroblasts (p<0.0005) and IPF parenchymal fibroblasts(p<0.05) compared to the healthy controls. Similarly, treatment with TGFβ1 significantly reduced TRPM7 mRNA expression in HLMFs (p<0.05, n=11). Functional TRPM7 currents are present in HLMFs and can be blocked with the addition of magnesium (6 mM) (n=6 IPF and n=13 NFC) and waixenicin A(500nM) (n=6). siRNA knockdown of TRPM7 inhibited TRPM7 function and decreased α-SMA, Collagen 1 and 6 mRNA (n=10). MTS showed waixenicin A has no cytotoxic effects on HLMFs (n=5). TRPM7 inhibition has no significant effect on proliferation of HLMFs but significantly impaired wound healing (p<0.01, n=7). In addition, changes in TRPM7 methylation (p<0.01) were observed in CpGs located in regulatory regions.Conclusion We confirmed HLMFs express functional TRPM7 channels. Despite TRPM7 mRNA downregulation in IPF, its inhibition reduces fibrotic markers and impairs wound healing, indicating a role in fibroblast activation. Epigenetic modifications may contribute to TRPM7 suppression in IPF. Further research is needed to understand how TRPM7 regulation influences fibrosis.