European Journal of Pharmacology
Cardiovascular diseases (CVDs) are the leading causes of mortality worldwide. As a type of CVDs, myocardial infarction (MI) induces ischemia hypoxia, which leads to excessive reactive oxygen species (ROS), resulting in multiple cell deaths and contributing to the subsequent development of heart failure or premature death. Recent evidence indicates that ROS-induced lipid peroxidation promotes autophagy and ferroptosis, leading to the loss of healthy myocardium and resulting in the dysfunction of cardiac tissue. Theoretically, cardiac function would be preserved after MI by inhibiting autophagy and ferroptosis. As an analog of coenzyme Q10 (CoQ10) and a clinically approved drug, idebenone would be used to inhibit ferroptosis and preserve cardiac function due to its capacity to improve mitochondrial physiology with antioxidant and anti-inflammatory properties. Here, we confirmed that the addition of idebenone inhibited H2O2-induced and RSL3-induced ferroptosis. Furthermore, the ROS-AMPK-mTOR pathway axis was identified as the signaling pathway that idebenone stimulated to prevent excessive autophagy and consequent ferroptosis. In the MI animal model, idebenone demonstrated a cardioprotective role by regulating ROS-dependent autophagy and inhibiting ferroptosis, which paves the way for the future clinical translation of idebenone in MI management.
Text reproduced verbatim from PubMed indexed abstract (source); DOI; CC-BY-4.0.
Demin Li, Ge Zhang, Zeyu Wang, Jiacheng Guo, Yu Liu, Yongzheng Lu, Zhen Qin, Yanyan Xu, Chang Cao, Bo Wang, Qianqian Guo, Yunzhe Wang, Guozhen Liu, Xiaolin Cui, Jinying Zhang, Junnan Tang. Idebenone attenuates ferroptosis by inhibiting excessive autophagy via the ROS-AMPK-mTOR pathway to preserve cardiac function after myocardial infarction. European Journal of Pharmacology. 2023;943:175569. https://doi.org/10.1016/j.ejphar.2023.175569
Idebenone attenuates ferroptosis by inhibiting excessive autophagy via the ROS-AMPK-mTOR pathway to preserve cardiac function after myocardial infarction
H9c2 injury models, pharmacologic pathway probes and LAD-ligation mouse experiments provide preclinical functional and mechanism-supporting evidence for idebenone. The animal regimen included pretreatment; these findings do not establish post-infarction-only rescue treatment or human MI efficacy, safety or approval.
Figure-level n is the reported unit for the corresponding experiment, not a study-wide deduplicated total. Cells, technical readouts and animals cannot be added together. This synthesis focuses on the reviewed core cellular and animal experiments; public-omics background analyses are not human drug-validation cohorts.
What cellular and mouse evidence supports idebenone-associated reduction of ferroptotic injury, and how does pretreatment timing limit translation to post-infarction clinical treatment?
This preclinical study used H9c2 injury models, pharmacologic pathway probes and LAD-ligation mouse experiments. Oxidative-injury, ferroptosis and autophagy readouts are distinguished from cardiac-function readouts. The animal regimen included dosing before surgery and is not evidence for treatment initiated only after infarction. The findings do not establish human myocardial-infarction efficacy, safety or an approved clinical indication.
H2O2-associated cell death is not exclusively ferroptosis, and these observations do not exclude other protective actions.
| Measure | Value |
|---|---|
| experimental system | H9c2 H2O2-associated injury |
| intervention timing | Idebenone pretreatment |
| readouts | Cell viability; ROS; lipid peroxidation |
Source locator: Author-deposited full text: Results 3.1-3.2; Figs. 1-2
This is experimental mechanistic support. Marker changes do not by themselves establish a complete, specific causal chain.
| Measure | Value |
|---|---|
| experimental probe | RSL3 |
| protein readouts | GPX4; FTH1; FPN1 |
| related controls | DFO; ferrostatin-1 |
Source locator: Author-deposited full text: Results 3.2 and 3.5; Figs. 2 and 7
Pharmacologic perturbations are not complete gene-specific validation. These results do not imply that all ferroptosis depends on autophagy.
| Measure | Value |
|---|---|
| pharmacologic probes | Metformin; rapamycin |
| pathway readouts | p-AMPK/AMPK; p-mTOR/mTOR |
| autophagy associated readouts | LC3; p62 |
Source locator: Author-deposited full text: Results 3.3-3.5; Figs. 3-7
This is a pretreatment-containing perioperative regimen, not a validated rescue regimen initiated exclusively after myocardial infarction. No dose recommendation or cross-species conversion is supplied.
| Measure | Value |
|---|---|
| model | LAD ligation |
| main groups | sham+vehicle; MI+vehicle; MI+idebenone |
| preoperative dosing | 24 h and 2 h before surgery |
| subsequent dosing | Continued after surgery |
| observation windows | Short-term and longer-term |
Source locator: Author-deposited full text: Methods 2.11-2.12; Results 3.6; Fig. 8A
The percentages are EF values themselves, not relative percentage improvements. Mouse cardiac-function and histological observations do not establish human survival benefit or clinical utility.
| Measure | Value |
|---|---|
| timepoint | 4 weeks |
| MI EF | 21.82% |
| MI plus idebenone EF | 33.76% |
| Fig 8 reported n | 5 |
| histology fibrosis | Qualitatively improved readouts |
Source locator: Author-deposited full text: Results 3.6; Fig. 8B-F
Readouts from different timepoints and materials cannot be treated as one continuous causal chain in a patient. Ambiguous fold-change wording is not recalculated into new effect sizes, and these tissue findings are not human clinical efficacy evidence.
| Measure | Value |
|---|---|
| oxidative iron readouts | ROS; MDA; Fe2+ |
| protein readouts | GPX4; FTH1; FPN1 |
| autophagy tissue readouts | LC3; p62; tissue observations |
Source locator: Author-deposited full text: Results 3.7-3.8; Figs. 9-10
H9c2 H2O2-injury experiments reported pretreatment-associated improvements in viability, ROS and lipid-peroxidation readouts. RSL3, GPX4/FTH1/FPN1 and DFO/ferrostatin-1-related controls support ferroptosis involvement, without making all oxidative cell death exclusively ferroptotic or establishing a complete specific causal chain.
Metformin/rapamycin experiments, p-AMPK/AMPK and p-mTOR/mTOR readouts, and LC3/p62 observations support the proposed pathway. Pharmacologic perturbations do not replace full gene-specific validation or imply that every instance of ferroptosis requires autophagy.
Evidence: KF3
The LAD-ligation regimen included idebenone 24 h and 2 h before surgery, then continued dosing; it was not exclusively post-infarction initiation. Four-week EF was reported as 21.82% for MI and 33.76% for MI+idebenone, with Fig. 8 n=5 and qualitative histological/fibrosis improvement. These are EF values in a pretreatment-containing mouse experiment, not relative survival improvements or proven clinical rescue efficacy.
Myocardial ROS/MDA/Fe2+, GPX4/FTH1/FPN1, LC3/p62 and tissue observations changed with intervention. Different materials and timepoints do not form a verified continuous causal chain in an individual patient; no new effect sizes are recalculated from ambiguous fold-change wording.
Evidence: KF6
| Row ID | Component | Context | Finding | Evidence Level | Scope | Source Locator | Evidence refs |
|---|---|---|---|---|---|---|---|
| evidence-idebenone-1 | Oxidative cellular injury | H2O2-associated cell death is not exclusively ferroptosis, and these observations do not exclude other protective actions. | Idebenone pretreatment reduced reported H2O2-associated injury in H9c2 cells, assessed using cell viability, ROS and lipid-peroxidation readouts. | Preclinical functional and mechanism-supporting evidence | Supports protection under the stated cellular conditions, not exclusive ferroptotic death or exclusion of other actions. | Author-deposited full text: Results 3.1-3.2; Figs. 1-2 | KF1 |
| evidence-idebenone-2 | Ferroptosis-focused cellular evidence | This is experimental mechanistic support. Marker changes do not by themselves establish a complete, specific causal chain. | RSL3 experiments, ferroptosis-related interventions and GPX4/FTH1/FPN1 readouts supported ferroptosis involvement; DFO/ferrostatin-1-related controls were described in the text. | Preclinical functional and mechanism-supporting evidence | Supports experimental mechanism involvement, not a fully specific causal chain from marker changes. | Author-deposited full text: Results 3.2 and 3.5; Figs. 2 and 7 | KF2 |
| evidence-idebenone-3 | Autophagy/pathway probes | Pharmacologic perturbations are not complete gene-specific validation. These results do not imply that all ferroptosis depends on autophagy. | Metformin/rapamycin experiments and AMPK-mTOR-related readouts supported the proposed pathway, alongside LC3/p62 and autophagy-associated observations. | Preclinical functional and mechanism-supporting evidence | Supports pharmacologic pathway involvement, not complete genetic validation or universal autophagy dependence. | Author-deposited full text: Results 3.3-3.5; Figs. 3-7 | KF3 |
| evidence-idebenone-4 | Animal timing and comparison | This is a pretreatment-containing perioperative regimen, not a validated rescue regimen initiated exclusively after myocardial infarction. No dose recommendation or cross-species conversion is supplied. | The LAD-ligation model used three main groups—sham+vehicle, MI+vehicle and MI+idebenone—with dosing 24 h and 2 h before surgery followed by continued dosing and short- and longer-term observations. | Preclinical functional and mechanism-supporting evidence | Applies to pretreatment-containing perioperative dosing, not post-infarction-only clinical rescue. | Author-deposited full text: Methods 2.11-2.12; Results 3.6; Fig. 8A | KF4 |
| evidence-idebenone-5 | Cardiac function and histology | The percentages are EF values themselves, not relative percentage improvements. Mouse cardiac-function and histological observations do not establish human survival benefit or clinical utility. | At four weeks, Results reported EF of 21.82% in MI and 33.76% in MI+idebenone, with Fig. 8 reporting n=5; histological/fibrosis readouts also improved qualitatively. | Preclinical functional and mechanism-supporting evidence | Supports mouse functional observations, not relative survival improvement or human benefit. | Author-deposited full text: Results 3.6; Fig. 8B-F | KF5 |
| evidence-idebenone-6 | Myocardial molecular readouts | Readouts from different timepoints and materials cannot be treated as one continuous causal chain in a patient. Ambiguous fold-change wording is not recalculated into new effect sizes, and these tissue findings are not human clinical efficacy evidence. | Myocardial oxidative, iron-handling and autophagy-associated readouts changed with intervention, including ROS/MDA/Fe2+, GPX4/FTH1/FPN1, LC3/p62 and tissue observations. | Preclinical functional and mechanism-supporting evidence | Supports tissue-level molecular observations without combining different materials into a human causal chain. | Author-deposited full text: Results 3.7-3.8; Figs. 9-10 | KF6 |
Idebenone pretreatment reduced reported H2O2-associated injury in H9c2 cells, assessed using cell viability, ROS and lipid-peroxidation readouts. H2O2-associated cell death is not exclusively ferroptosis, and these observations do not exclude other protective actions.
Evidence: KF1
RSL3 experiments, ferroptosis-related interventions and GPX4/FTH1/FPN1 readouts supported ferroptosis involvement; DFO/ferrostatin-1-related controls were described in the text. This is experimental mechanistic support. Marker changes do not by themselves establish a complete, specific causal chain.
Evidence: KF2
Metformin/rapamycin experiments and AMPK-mTOR-related readouts supported the proposed pathway, alongside LC3/p62 and autophagy-associated observations. Pharmacologic perturbations are not complete gene-specific validation. These results do not imply that all ferroptosis depends on autophagy.
Evidence: KF3
The LAD-ligation model used three main groups—sham+vehicle, MI+vehicle and MI+idebenone—with dosing 24 h and 2 h before surgery followed by continued dosing and short- and longer-term observations. This is a pretreatment-containing perioperative regimen, not a validated rescue regimen initiated exclusively after myocardial infarction. No dose recommendation or cross-species conversion is supplied.
Evidence: KF4
At four weeks, Results reported EF of 21.82% in MI and 33.76% in MI+idebenone, with Fig. 8 reporting n=5; histological/fibrosis readouts also improved qualitatively. The percentages are EF values themselves, not relative percentage improvements. Mouse cardiac-function and histological observations do not establish human survival benefit or clinical utility.
Evidence: KF5
Myocardial oxidative, iron-handling and autophagy-associated readouts changed with intervention, including ROS/MDA/Fe2+, GPX4/FTH1/FPN1, LC3/p62 and tissue observations. Readouts from different timepoints and materials cannot be treated as one continuous causal chain in a patient. Ambiguous fold-change wording is not recalculated into new effect sizes, and these tissue findings are not human clinical efficacy evidence.
Evidence: KF6
Study-level author-maintained evidence summary. Not participant-level data and not a ready-to-pool meta-analysis dataset. For formal citation, use the original article DOI.
Download study-level evidence CSV (UTF-8)Formula safety: cells starting with =, +, -, @ (after leading whitespace), or tab/CR/LF are prefixed with an apostrophe. Treat all cells as text; remove only that safety prefix when recovering the original string.
These records identify the same original work; database inclusion is not evidence of scientific validity or clinical benefit.