CircHIPK3 regulates pulmonary fibrosis by facilitating glycolysis in miR-30a-3p/FOXK2-dependent manner

Abstract

Pulmonary fibrosis develops when myofibroblasts and extracellular matrix excessively accumulate in the injured lung, but what drives fibrosis is not fully understood. Glycolysis has been linked to cell growth and proliferation, and several studies have shown enhanced glycolysis promotes pulmonary fibrosis. However, detailed studies describing this switch remain limited. Here, we identified that TGF-β1 effectively increased the expression of circHIPK3 in lung fibroblasts, and circHIPK3 inhibition attenuated the activation, proliferation, and glycolysis of fibroblasts in vitro. Dual-luciferase reporter gene assays, RNA immunoprecipitation (RIP), and RNA pull-down assays showed that circHIPK3 could function as a sponge of miR-30a-3p and inhibit its expression. Furthermore, FOXK2, a driver transcription factor of glycolysis, was identified to be a direct target of miR-30a-3p. Mechanistically, circHIPK3 could enhance the expression of FOXK2 via sponging miR-30a-3p, thereby facilitating fibroblast glycolysis and activation. Besides, miR-30a-3p overexpression or FOXK2 knockdown blocked fibroblast activation induced by TGF-β1 and abrogated the profibrotic effects of circHIPK3. Moreover, circHIPK3 and miR-30a-3p were also dysregulated in fibrotic murine lung tissues induced by silica. Adeno-associated virus (AAV)mediated circHIPK3 silence or miR-30a-3p overexpression alleviated silica-induced pulmonary fibrosis in vivo. In conclusion, our results identified circHIPK3/miR-30a-3p/FOXK2 regulatory pathway as an important glycolysis cascade in pulmonary fibrosis.

Study on the Correlation between Interleukin-27 and CXCL10 in Pulmonary Tuberculosis

“…In addition, miR-30a-3p was negatively correlated with IL-27 and CXCL10 ( Figure 6(d) ); this also attracts our attention. In recent years, miR-30a-3p has made some progress in tumors [ 31 – 33 ], and it also has a certain research basis for asthma and pulmonary fibrosis [ 34 , 35 ]. However, in this bioinformatics study on TB, we discovered 13 key genes involved in the network relationship between IL-27 and CXCL10.…”

Identification of a circRNA/miRNA/mRNA ceRNA Network as a Cell Cycle-Related Regulator for Chronic Sinusitis with Nasal Polyps

“… 3 It is widely reported that circRNA plays an important role in cell and tissue proliferation. 4 , 5 For example, circGCN1L1 promotes cell proliferation and apoptosis by targeting miR-330-3p and TNF-α. 6 CircRNAs play important roles in CRSwNP occurrence.…”

Glycolytic Reprogramming in Silica-Induced Lung Macrophages and Silicosis Reversed by Ac-SDKP Treatment

“…However, the role of glycolysis in silicosis is still unclear. The lactate levels and the protein expression levels of glycolytic enzymes, including HK2, phosphofructokinase muscle (PFKM), PKM2, and pyruvate dehydrogenase kinase isozyme1 (PDK1), were enhanced in TGF-β1-induced MRC-5 fibroblasts and in mice exposed to silica [8]. The high levels of HK2 and PKM2 in silicotic mice were attenuated by triiodothyronine (T3) treatment [9].…”

“…Augmentation of glycolysis is an early and sustained event during myofibroblast differentiation in lung fibrosis [7]. Furthermore, the interaction between glycolysis and collagen deposition has been demonstrated in TGF-β1-induced lung fibroblasts and silica-treated mice [8,9]. Although it is acknowledged that glycolysis occurs in silicosis, the exact mechanism driving glycolysis in lung macrophages or lung inflammation remains largely unknown.…”