HOX and MEINOX in cellular plasticity, fibrosis, and cancer

Table 3 The effects of non-coding HOX genes in various fibrotic diseases

HOX genes	Disease	Mode of function in fibrosis	Proof of concept or mechanism of action	Ref.
HOTAIR	Liver fibrosis	Pro-fibrotic	HOTAIR upregulation was found to be promoting liver fibrosis in mouse and cell line models. Arsenic exposure was found to induce hepatic fibrosis via T-cell expression of HOTAIR	[177,201,202]
	Lung fibrosis	Pro-fibrotic	Acts as a competing ceRNA to regulate MMP2 expression during paraquat-induced lung epithelial-mesenchymal transition, promoting fibrosis	[203]
	Kidney fibrosis	Pro-fibrotic	In a rat model with TGFβ-treated kidney cells, HOTAIR was elevated in renal fibrosis, driving epithelial-mesenchymal transition via the Notch pathway	[109]
	Cardiac fibrosis	Pro-fibrotic	Upregulated in atrial fibrillation and promotes pathological fibrosis in the atrium. In Ang II-treated atrial fibroblasts, HOTAIR and Wnt5a levels increased, and HOTAIR knockdown inhibited fibroblast proliferation, migration, and expression of collagen I/III and α-SMA	[12]
	Skin fibrosis	Pro-fibrotic	In systemic sclerosis dermal fibroblasts, HOTAIR is aberrantly upregulated and induces a pro-fibrotic gene program. Overexpression of HOTAIR in healthy skin fibroblasts caused epigenetic silencing of miR-34a via EZH2 (H3K27me3), which activated Notch signaling and secondarily upregulated the Hedgehog effector GLI2	[91,204]
HOTAIRM1	Lung fibrosis	Pro-fibrotic	Hypoxia-exposed alveolar epithelial cells secrete pro-fibrotic exosomes enriched in lncRNA HOTAIRM1	[205]
HOTTIP	Liver fibrosis	Pro-fibrotic	Promotes hepatic stellate cell activation through increased SRF expression by sponging miR-150	[206]
	Liver fibrosis	Pro-fibrotic	Highly upregulated in fibrotic livers and activated hepatic stellate cells. Increased HOTTIP acts as a sponge for miR-148a, relieving repression of TGFβ receptor genes. Consequently, TGFBR1/2 levels rise, driving HSC activation and collagen production	[112]
	Lung fibrosis	Pro-fibrotic	Enhances lung fibrosis by regulating the miR-744-5p/PTBP1 signaling axis	[110]
HOXA11-AS	Liver fibrosis	Pro-fibrotic	Upregulated in a mouse model of ischemia/reperfusion-induced liver fibrosis and exacerbates fibrosis via a PTBP1/HDAC4 mechanism	[167]
	Cardiac fibrosis	Pro-fibrotic	Drives TGFβ1-mediated cardiac fibroblast activation. Overexpression of HOXA11-AS in mouse cardiac fibroblasts significantly increased TGF-β1 expression and downstream Smad signaling, promoting fibroblast proliferation, colony formation, and invasion, whereas HOXA11-AS knockdown had opposite effects	[106]
	Skin fibrosis	Pro-fibrotic	Significantly overexpressed in keloid tissue and fibroblasts, promotes abnormal scar formation by acting as a ceRNA	[207]
miR-10a	Liver fibrosis	Pro-fibrotic	In a CCl4-induced mouse liver fibrosis model, miR-10a was found to exacerbate fibrosis. Overexpression of miR-10a increased TGF-β1/Smad3 signaling and collagen-I expression, whereas miR-10a inhibition ameliorated liver fibrosis	[197]
miR-10a/b	Kidney fibrosis	Pro-fibrotic	miR-10 family (miR-10a/10b, located in HOX clusters) is aberrantly expressed in chronic kidney disease. In fibrotic mouse kidneys, miR-10a/b levels are elevated and contribute to fibrosis by targeting VASH1, an anti-angiogenic factor that also inhibits TGF-β/Smad signaling	[114]
miR-196a	Lung fibrosis	Anti-fibrotic	In a bleomycin-induced fibrosis model, lncRNA H19 was upregulated and sponged miR-196a, thereby relieving suppression of COL1A1. Silencing H19 reduced fibroblast activation and collagen deposition, an effect reversed by miR-196a inhibition	[208]
miR-615-5p	Liver fibrosis	Pro-fibrotic	miR-615-5p expression is significantly upregulated in cirrhotic livers and in plasma of patients with advanced fibrosis compared to healthy controls	[209]

ceRNA: Competitive endogenous RNA; MMP: Matrix metalloproteinase; TGF: Transforming growth factor; α-SMA: Alpha-smooth muscle actin; EZH2: Enhancer of zeste homolog 2; GLI2: Glioma-associated oncogene homolog 2; SRF: Serum response factor; TGFBR1/2: Transforming growth factor-beta receptor 1/2; PTBP1: Polypyrimidine tract-binding protein 1; HDAC4: Histone deacetylation 4; VASH1: Vasohibin 1; lncRNA: Long non-coding RNA; COL1A1: Collagen type 1.