Dihydroquercetin Attenuates Silica-Induced Pulmonary Fibrosis by Inhibiting Ferroptosis Signaling Pathway

Abstract

Silicosis is a fatal occupational lung disease which currently has no effective treatment. Dihydroquercetin (DHQ) is a flavonoid compound known for its anti-inflammatory, anti-oxidant and anti-cancer bioactivity. However, whether DHQ protects against silica-induced lung fibrosis remains unknown. Therefore, we aimed to investigate the effect of DHQ on silica-induced lung fibrosis and the underlying molecular mechanism in vivo and in vitro. Our results demonstrated that DHQ treatment markedly attenuated SiO2-induced inflammation and fibrosis degree of lung tissues in the C57BL/6 mice. Additionally, experiments in vitro also confirmed that conditioned medium from DHQ-treated human bronchial epithelial (HBE) cells significantly decreased expression of fibrosis markers of human fetal lung fibroblast cells (MRC-5), such as α-SMA, collagen1 and fibronectin. Interestingly, HBE cells treated by DHQ showed few morphological features of ferroptosis compared with SiO2-treated cells. Furthermore, DHQ treatment remarkably inhibited ferroptosis in activated HBE cells by decreasing the accumulation of iron and lipid peroxidation products, and increasing levels of glutathione (GSH) and glutathione peroxidase 4 (GPX4), whereas stimulation of ferroptosis by specific inducer erastin deeply impaired anti-fibrosis effect of DHQ in vitro. More importantly, our results showed that DHQ also evidently suppressed ferritinophagy by down-regulation of microtubule-associated protein 1A/1B-light chain 3 (LC3), and up-regulation of ferritin heavy chain 1 (FTH1), nuclear receptor co-activator 4 (NCOA4) in activated HBE cells. Nevertheless, activation of ferritinophagy by specific inducer rapamycin (Rapa) evidently blocked DHQ-inhibited HBE cells ferritinophagy and anti-fibrosis effect of DHQ. Overall, our research revealed that inhibition of ferritinophagy-mediated HBE cells ferroptosis was responsible for DHQ to ameliorate SiO2-induced lung fibrosis, which provided a preliminary theoretical basis for the clinical application of DHQ in the treatment of silicosis.

Hydrogen sulfide alleviates beryllium sulfate‐induced ferroptosis and ferritinophagy in 16HBE cells

“…In recent years, researchers' interests have increasingly focused on the molecular mechanisms of ferroptosis and ferritinophagy, alongside the prevention and treatment of various related diseases. Relevant studies reported that ferroptosis is associated with various lung diseases, including acute lung injury, pulmonary fibrosis, COPD, pulmonary heart disease, and lung cancer (Brown et al, 2019; Yatmark et al, 2015; Yoshida et al, 2019; L. Yuan et al, 2022). According to previous reported, whole cigarette smoke condensates induced ferroptosis in bronchial epithelial cells via endoplasmic reticulum stress and mitochondrial dynamic cause by induction of hypoxic conditions (Park et al, 2019).…”

“…This process eventually triggers ferroptosis. Although the relationship between ferroptosis and beryllium disease is not well defined, its role in lung diseases has been established, including acute lung injury, pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), pulmonary heart disease, and lung cancer (Brown et al, 2019; Xu et al, 2021; Yoshida et al, 2019; L. Yuan et al, 2022). For example, whole cigarette smoke condensates induced ferroptosis in bronchial epithelial cells through endoplasmic reticulum stress and the hypoxic‐induced disturbance of mitochondrial dynamic homeostasis (Park et al, 2019).…”

Natural Flavonoids and Ferroptosis: Potential Therapeutic Opportunities for Human Diseases

“…Dihydroquercetin, a plant flavanonol isolated from yew, protected against SiO 2 -induced lung fibrosis in C57BL/6 mice. 133 Mechanistically, dihydroquercetin inhibited ferritinophagy by reducing the expression of microtubule-associated protein 1A/1B light chain 3 (LC3), thereby alleviating iron accumulation and lipid peroxidation in bronchial epithelial cells. Moreover, glabridin from licorice could ameliorate glucose metabolism and renal injury in diabetic rats by inhibiting ferroptosis, which was associated with the decreased expression of TFR and the increased expression of SLC3A2, SLC7A11, and GPX4 in renal tissues.…”

“…Further studies confirmed that silibinin could suppress the enzymatic activity of ACSL4 by directly binding to it, which inhibited ferroptosis in hepatocytes and thus exerted hepatoprotective effects. Dihydroquercetin, a plant flavanonol isolated from yew, protected against SiO 2 -induced lung fibrosis in C57BL/6 mice . Mechanistically, dihydroquercetin inhibited ferritinophagy by reducing the expression of microtubule-associated protein 1 A /1B light chain 3 (LC3), thereby alleviating iron accumulation and lipid peroxidation in bronchial epithelial cells.…”

Physiological Effects of Ferroptosis on Organ Fibrosis

“…A study reported that ferroptosis inhibitors effectively circumvent the toxicity of paraquat, and ferroptotic death may have a considerable contribution to paraquat-mediated pathological changes in lung tissue [100]. According to a recently study, dihydroquercetin has significant efficacy against silica-induced pulmonary fibrosis, ameliorating fibrotic manifestations by 10 Oxidative Medicine and Cellular Longevity inhibiting ferritinophagy-mediated ferroptosis in human bronchial epithelial cells [101]. damage to ATII cells is involved in the process of lung fibrosis.…”