General Information of the Disease (ID: DIS00106)
Name
Pulmonary fibrosis
ICD
ICD-11: CB03
Full List of Target(s) of This Ferroptosis-centered Disease
Nuclear receptor coactivator 4 (NCOA4)
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [1]
Target for Ferroptosis Driver
Responsed Disease Chronic obstructive pulmonary disease complicated with atherosclerosis [ICD-11: CB03]
Responsed Drug Dihydroquercetin Preclinical
Responsed Regulator Microtubule-associated proteins 1A/1B light chain 3A (MAP1LC3A) Driver
Pathway Response Fatty acid metabolism hsa01212
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model hBEs (Human bronchial epithelial cells)
MRC-5 cells Normal Homo sapiens CVCL_0440
In Vivo Model
Eight-week-old male C57BL/6 mice were purchased from Hubei University of Medicine (Shiyan, China). The SiO2-induced mouse pulmonary fibrosis model was performed. In brief, each group of mice was anesthetized with 1% pentobarbital sodium intraperitoneally at 40 mg/kg body weight and their tracheae had been surgically exposed. In addition, SiO2 suspension (20 mg in 50 ul saline) was instilled in the mice. The vehicle control groups were given an equivalent amount of 0.9% sterile saline. After one week of acclimation, mice were divided randomly into four groups (n = 8 per group). Control group, SiO2 group, SiO2 and low dose of DHQ group (DHQ-L, 10 mg/kg) as well as large dose of DHQ group (DHQ-H, 50 mg/kg).

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Response regulation Dihydroquercetin 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. Research revealed that inhibition of ferritinophagy-mediated HBE cells ferroptosis was responsible for DHQ to ameliorate SiO2-induced lung fibrosis.
Ferritin heavy chain (FTH1)
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [1]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Chronic obstructive pulmonary disease complicated with atherosclerosis [ICD-11: CB03]
Responsed Drug Dihydroquercetin Preclinical
Responsed Regulator Microtubule-associated proteins 1A/1B light chain 3A (MAP1LC3A) Driver
Pathway Response Fatty acid metabolism hsa01212
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model hBEs (Human bronchial epithelial cells)
MRC-5 cells Normal Homo sapiens CVCL_0440
In Vivo Model
Eight-week-old male C57BL/6 mice were purchased from Hubei University of Medicine (Shiyan, China). The SiO2-induced mouse pulmonary fibrosis model was performed. In brief, each group of mice was anesthetized with 1% pentobarbital sodium intraperitoneally at 40 mg/kg body weight and their tracheae had been surgically exposed. In addition, SiO2 suspension (20 mg in 50 ul saline) was instilled in the mice. The vehicle control groups were given an equivalent amount of 0.9% sterile saline. After one week of acclimation, mice were divided randomly into four groups (n = 8 per group). Control group, SiO2 group, SiO2 and low dose of DHQ group (DHQ-L, 10 mg/kg) as well as large dose of DHQ group (DHQ-H, 50 mg/kg).

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Response regulation Dihydroquercetin 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. Research revealed that inhibition of ferritinophagy-mediated HBE cells ferroptosis was responsible for DHQ to ameliorate SiO2-induced lung fibrosis.
Transferrin receptor protein 1 (TFRC)
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [2]
Target for Ferroptosis Marker/Suppressor/Driver
Responsed Disease Pulmonary fibrosis [ICD-11: CB03]
Responsed Drug Bleomycin Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model MLE-12 cells Normal Mus musculus CVCL_3751
In Vivo Model
C57BL/6 J mice (8-week old) from SLAC Laboratory Animal Co. LTD (Shanghai, China) were housed in a specific pathogen-free (SPF) barrier system at 20 with 12-h light/dark cycles. They were randomly grouped as follows: (1) intratracheal saline (control group); (2) intraperitoneal deferoxamine (DFO, Sigma-Aldrich; DFO group); (3) intratracheal bleomycin (BLM, Nippon Kayaku Co., Ltd.; BLM group); and (4) intratracheal BLM plus intraperitoneal deferoxamine (BLM + DFO group). They were intratracheally injected with 50 ul of BLM (5 mg/kg) on day 0. For the preventive anti-fibrotic treatment, DFO (50 mg/kg2 day-1) was administered from day 0 to day 20. Lung samples were collected at day 21.

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Response regulation Bleomycin (BLM) can induce the inhibition of cellular GPX4, leading to the generation of lipid ROS. Besides, BLM treatment significantly increased the expression levels of ACSL4 but similarly decreased those of FSP1. TfR1 expression was significantly increased by BLM treatment but decreased by BLM + DFO treatment. These findings indicate that iron metabolism disorder, iron deposition, and ferroptosis in ATII cells may be involved in the pathogenesis of BLM-induced pulmonary fibrosis.
Solute carrier family 40 member 1 (SLC40A1)
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [2]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Pulmonary fibrosis [ICD-11: CB03]
Responsed Drug Bleomycin Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model MLE-12 cells Normal Mus musculus CVCL_3751
In Vivo Model
C57BL/6 J mice (8-week old) from SLAC Laboratory Animal Co. LTD (Shanghai, China) were housed in a specific pathogen-free (SPF) barrier system at 20 with 12-h light/dark cycles. They were randomly grouped as follows: (1) intratracheal saline (control group); (2) intraperitoneal deferoxamine (DFO, Sigma-Aldrich; DFO group); (3) intratracheal bleomycin (BLM, Nippon Kayaku Co., Ltd.; BLM group); and (4) intratracheal BLM plus intraperitoneal deferoxamine (BLM + DFO group). They were intratracheally injected with 50 ul of BLM (5 mg/kg) on day 0. For the preventive anti-fibrotic treatment, DFO (50 mg/kg2 day-1) was administered from day 0 to day 20. Lung samples were collected at day 21.

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Response regulation Bleomycin (BLM) can induce the inhibition of cellular GPX4, leading to the generation of lipid ROS. Besides, BLM treatment significantly increased the expression levels of TfR1 and DMT1 in a concentration- and time-dependent manner but similarly decreased those of FPN. TfR1 expression was significantly increased by BLM treatment but decreased by BLM + DFO treatment. These findings indicate that iron metabolism disorder, iron deposition, and ferroptosis in ATII cells may be involved in the pathogenesis of BLM-induced pulmonary fibrosis.
Sodium-coupled neutral amino acid symporter 1 (SLC38A1)
In total 2 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [3]
Target for Ferroptosis Driver
Responsed Disease Chronic obstructive pulmonary disease complicated with atherosclerosis [ICD-11: CB03]
Responsed Regulator ZFAS1 (IncRNA) Driver
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
Cell migration
In Vitro Model HFL1 cells Normal Homo sapiens CVCL_0298
In Vivo Model
Male Sprague-Dawley rats (200-220 g) were purchased from Weitonglihua Company (Beijing, China) and maintained in a pathogen-free facility. After one week of adaptive feeding, a total of 30 rats were randomly divided into 3 groups (n = 10 rats/group): a control group; bleomycin (BLM) group; and BLM + sh-ZFAS1 group. Rats in the BLM group were administered 5 mg/kg BLM (Nippon Kayaku, Japan) dissolved in phosphate buffered saline (PBS) and administered to the rats intratracheally to establish the PF model. Rats in the control group were treated with 0.05 mL PBS. Rats in the BLM + sh-ZFAS1 group were injected intraperitoneally with 30 uL lncRNA ZFAS1 shRNA adeno-associated virus 5 (Vigene Biosciences, USA) for 3 weeks prior to an injection of 5 mg/kg BLM sulfate.

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Response regulation Inhibition of lncRNA ZFAS1 abolished BLM-induced lipid peroxidation and pulmonary fibrosis (PF) development. Mechanistically, silencing of lncRNA ZFAS1 attenuated ferroptosis and PF progression by lncRNA ZFAS1 acting as a competing endogenous RNA (ceRNA) and sponging miR-150-5p to downregulate SLC38A1 expression.
Experiment 2 Reporting the Ferroptosis-centered Disease Response by This Target [3]
Target for Ferroptosis Driver
Responsed Disease Chronic obstructive pulmonary disease complicated with atherosclerosis [ICD-11: CB03]
Responsed Regulator hsa-miR-150-5p (miRNA) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
Cell migration
In Vitro Model HFL1 cells Normal Homo sapiens CVCL_0298
In Vivo Model
Male Sprague-Dawley rats (200-220 g) were purchased from Weitonglihua Company (Beijing, China) and maintained in a pathogen-free facility. After one week of adaptive feeding, a total of 30 rats were randomly divided into 3 groups (n = 10 rats/group): a control group; bleomycin (BLM) group; and BLM + sh-ZFAS1 group. Rats in the BLM group were administered 5 mg/kg BLM (Nippon Kayaku, Japan) dissolved in phosphate buffered saline (PBS) and administered to the rats intratracheally to establish the PF model. Rats in the control group were treated with 0.05 mL PBS. Rats in the BLM + sh-ZFAS1 group were injected intraperitoneally with 30 uL lncRNA ZFAS1 shRNA adeno-associated virus 5 (Vigene Biosciences, USA) for 3 weeks prior to an injection of 5 mg/kg BLM sulfate.

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Response regulation Inhibition of lncRNA ZFAS1 abolished BLM-induced lipid peroxidation and pulmonary fibrosis (PF) development. Mechanistically, silencing of lncRNA ZFAS1 attenuated ferroptosis and PF progression by lncRNA ZFAS1 acting as a competing endogenous RNA (ceRNA) and sponging miR-150-5p to downregulate SLC38A1 expression.
Natural resistance-associated macrophage protein 2 (SLC11A2)
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [2]
Target for Ferroptosis Driver
Responsed Disease Pulmonary fibrosis [ICD-11: CB03]
Responsed Drug Bleomycin Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model MLE-12 cells Normal Mus musculus CVCL_3751
In Vivo Model
C57BL/6 J mice (8-week old) from SLAC Laboratory Animal Co. LTD (Shanghai, China) were housed in a specific pathogen-free (SPF) barrier system at 20 with 12-h light/dark cycles. They were randomly grouped as follows: (1) intratracheal saline (control group); (2) intraperitoneal deferoxamine (DFO, Sigma-Aldrich; DFO group); (3) intratracheal bleomycin (BLM, Nippon Kayaku Co., Ltd.; BLM group); and (4) intratracheal BLM plus intraperitoneal deferoxamine (BLM + DFO group). They were intratracheally injected with 50 ul of BLM (5 mg/kg) on day 0. For the preventive anti-fibrotic treatment, DFO (50 mg/kg2 day-1) was administered from day 0 to day 20. Lung samples were collected at day 21.

    Click to Show/Hide
Response regulation Bleomycin (BLM) can induce the inhibition of cellular GPX4, leading to the generation of lipid ROS. Besides, BLM treatment significantly increased the expression levels of TfR1 and DMT1 in a concentration- and time-dependent manner but similarly decreased those of FPN. TfR1 expression was significantly increased by BLM treatment but decreased by BLM + DFO treatment. These findings indicate that iron metabolism disorder, iron deposition, and ferroptosis in ATII cells may be involved in the pathogenesis of BLM-induced pulmonary fibrosis.
Long-chain-fatty-acid--CoA ligase 4 (ACSL4)
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [2]
Target for Ferroptosis Driver
Responsed Disease Pulmonary fibrosis [ICD-11: CB03]
Responsed Drug Bleomycin Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model MLE-12 cells Normal Mus musculus CVCL_3751
In Vivo Model
C57BL/6 J mice (8-week old) from SLAC Laboratory Animal Co. LTD (Shanghai, China) were housed in a specific pathogen-free (SPF) barrier system at 20 with 12-h light/dark cycles. They were randomly grouped as follows: (1) intratracheal saline (control group); (2) intraperitoneal deferoxamine (DFO, Sigma-Aldrich; DFO group); (3) intratracheal bleomycin (BLM, Nippon Kayaku Co., Ltd.; BLM group); and (4) intratracheal BLM plus intraperitoneal deferoxamine (BLM + DFO group). They were intratracheally injected with 50 ul of BLM (5 mg/kg) on day 0. For the preventive anti-fibrotic treatment, DFO (50 mg/kg2 day-1) was administered from day 0 to day 20. Lung samples were collected at day 21.

    Click to Show/Hide
Response regulation Bleomycin (BLM) can induce the inhibition of cellular GPX4, leading to the generation of lipid ROS. Besides, BLM treatment significantly increased the expression levels of ACSL4 but similarly decreased those of FSP1. TfR1 expression was significantly increased by BLM treatment but decreased by BLM + DFO treatment. These findings indicate that iron metabolism disorder, iron deposition, and ferroptosis in ATII cells may be involved in the pathogenesis of BLM-induced pulmonary fibrosis.
Ferroptosis suppressor protein 1 (AIFM2)
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [2]
Target for Ferroptosis Suppressor
Responsed Disease Pulmonary fibrosis [ICD-11: CB03]
Responsed Drug Bleomycin Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model MLE-12 cells Normal Mus musculus CVCL_3751
In Vivo Model
C57BL/6 J mice (8-week old) from SLAC Laboratory Animal Co. LTD (Shanghai, China) were housed in a specific pathogen-free (SPF) barrier system at 20 with 12-h light/dark cycles. They were randomly grouped as follows: (1) intratracheal saline (control group); (2) intraperitoneal deferoxamine (DFO, Sigma-Aldrich; DFO group); (3) intratracheal bleomycin (BLM, Nippon Kayaku Co., Ltd.; BLM group); and (4) intratracheal BLM plus intraperitoneal deferoxamine (BLM + DFO group). They were intratracheally injected with 50 ul of BLM (5 mg/kg) on day 0. For the preventive anti-fibrotic treatment, DFO (50 mg/kg2 day-1) was administered from day 0 to day 20. Lung samples were collected at day 21.

    Click to Show/Hide
Response regulation Bleomycin (BLM) can induce the inhibition of cellular GPX4, leading to the generation of lipid ROS. Besides, BLM treatment significantly increased the expression levels of ACSL4 but similarly decreased those of FSP1. TfR1 expression was significantly increased by BLM treatment but decreased by BLM + DFO treatment. These findings indicate that iron metabolism disorder, iron deposition, and ferroptosis in ATII cells may be involved in the pathogenesis of BLM-induced pulmonary fibrosis.
Unspecific Target
In total 2 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [4]
Responsed Disease Chronic obstructive pulmonary disease complicated with atherosclerosis [ICD-11: CB03]
Responsed Regulator Histone-lysine N-methyltransferase SETDB1 (SETDB1) Driver
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell adhesion molecules hsa04514
Cell Process Cell ferroptosis
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
In Vivo Model
Forty Sprague-Dawley rats (weight 200 ± 20 g) were obtained from the Experimental Animal Center of Henan Province. The pulmonary fibrosis rat model was established using previously described techniques. The rats were administered a tracheal infusion of bleomycin at a concentration of 5 mg/kg in sterile 0.9% NaCl.

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Response regulation The epithelial-mesenchymal transition (EMT) is an important pathological process in the occurrence of pulmonary fibrosis. SETDB1 regulates the expression of Snai1 by catalyzing the histone H3 lysine 9 trimethylation (H3K9me3) of Snai1, the main transcription factor that initiates the process of EMT, and thus, indirectly regulates E-cadherin (CDH1). And overexpressed SETDB1 alleviated EMT and also caused ferroptosis.
Experiment 2 Reporting the Ferroptosis-centered Disease Response by This Target [4]
Responsed Disease Chronic obstructive pulmonary disease complicated with atherosclerosis [ICD-11: CB03]
Responsed Regulator Cadherin-1 (CDH1) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell adhesion molecules hsa04514
Cell Process Cell ferroptosis
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
In Vivo Model
Forty Sprague-Dawley rats (weight 200 ± 20 g) were obtained from the Experimental Animal Center of Henan Province. The pulmonary fibrosis rat model was established using previously described techniques. The rats were administered a tracheal infusion of bleomycin at a concentration of 5 mg/kg in sterile 0.9% NaCl.

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Response regulation The epithelial-mesenchymal transition (EMT) is an important pathological process in the occurrence of pulmonary fibrosis. SETDB1 regulates the expression of Snai1 by catalyzing the histone H3 lysine 9 trimethylation (H3K9me3) of Snai1, the main transcription factor that initiates the process of EMT, and thus, indirectly regulates E-cadherin (CDH1). And overexpressed SETDB1 alleviated EMT and also caused ferroptosis.
References
Ref 1 Dihydroquercetin Attenuates Silica-Induced Pulmonary Fibrosis by Inhibiting Ferroptosis Signaling Pathway. Front Pharmacol. 2022 May 12;13:845600. doi: 10.3389/fphar.2022.845600. eCollection 2022.
Ref 2 Iron deposition-induced ferroptosis in alveolar type II cells promotes the development of pulmonary fibrosis. Biochim Biophys Acta Mol Basis Dis. 2021 Dec 1;1867(12):166204. doi: 10.1016/j.bbadis.2021.166204. Epub 2021 Jun 24.
Ref 3 lncRNA ZFAS1 promotes lung fibroblast-to-myofibroblast transition and ferroptosis via functioning as a ceRNA through miR-150-5p/SLC38A1 axis. Aging (Albany NY). 2020 May 26;12(10):9085-9102. doi: 10.18632/aging.103176. Epub 2020 May 26.
Ref 4 Histone methyltransferase SETDB1 inhibits TGF--induced epithelial-mesenchymal transition in pulmonary fibrosis by regulating SNAI1 expression and the ferroptosis signaling pathway. Arch Biochem Biophys. 2022 Jan 15;715:109087. doi: 10.1016/j.abb.2021.109087. Epub 2021 Nov 18.