Triclosan exacerbates post-myocardial infarction injury via Nur77 ubiquitination: Linking NTRK2/PGC-1α-mediated mitochondrial dysfunction to senescence and ferroptosis.

Environmentally relevant TCS concentrations dose-dependently aggravated post-MI cardiac dysfunction and ventricular remodeling in both male and female mice.

• MI models were established using left anterior descending coronary artery ligation in mice.
• TCS exposure exacerbated both short-term and long-term post-MI cardiac dysfunction.
• The adverse effects were observed in both male and female mice.
• Echocardiography was used to assess cardiac function and ventricular remodeling.

TCS induced TRIM13-mediated K48-linked ubiquitination and proteasomal degradation of the nuclear receptor Nur77.

• TCS promoted TRIM13-mediated ubiquitination specifically via K48-linked polyubiquitin chains on Nur77.
• K48-linked ubiquitination targets proteins for proteasomal degradation.
• Mechanistic investigations utilized Nur77 knockout mice and co-immunoprecipitation assays.
• Molecular docking and Western blotting were employed to confirm the interaction and degradation.

Nur77 degradation led to reduced transcription of NTRK2, suppressing the AKT/mTOR/YY1 signaling cascade and decreasing PGC-1α expression.

• Downregulated NTRK2 suppressed the AKT/mTOR/YY1 signaling axis.
• Decreased PGC-1α expression impaired mitochondrial function, specifically mitochondrial oxidative phosphorylation.
• Dual-luciferase reporter assays and quantitative real-time PCR were used to validate transcriptional regulation.
• AAV9-based viral vectors targeting Nur77 and NTRK2 were used in mechanistic investigations.

Mitochondrial dysfunction caused by impaired PGC-1α expression triggered excessive ROS production, promoting lipid peroxidation and exacerbating cardiomyocyte ferroptosis.

• The bioenergetic deficit from impaired mitochondrial oxidative phosphorylation led to excessive reactive oxygen species (ROS) production.
• Elevated ROS promoted lipid peroxidation, a hallmark of ferroptosis.
• Oxidative stress parameter analyses and histological/immunofluorescence staining were used to assess these outcomes.
• Ferroptosis was confirmed in both neonatal rat cardiomyocytes (NRCMs) and human AC16 cardiomyocytes.

TCS exposure promoted cellular senescence and the senescence-associated secretory phenotype (SASP) in cardiomyocytes, contributing to long-term ventricular remodeling.

• ROS-mediated damage promoted both ferroptosis and cellular senescence in cardiomyocytes.
• The senescence-associated secretory phenotype (SASP) was identified as a pathological consequence.
• These effects collectively exacerbated acute post-MI injury and facilitated progression of long-term ventricular remodeling.
• RNA sequencing was among the comprehensive methodologies used to characterize these pathological changes.

Pharmacological activation of PGC-1α with ZLN005 mitigated TCS-induced deterioration of post-MI cardiac function and attenuated ventricular remodeling.

• ZLN005, a small-molecule PGC-1α activator, was used as a pharmacological intervention.
• ZLN005 treatment mitigated both short-term and long-term TCS-induced deterioration of post-MI cardiac function.
• Ventricular remodeling was attenuated by ZLN005 treatment.
• These findings suggest PGC-1α activation as a potential preventive strategy against TCS-induced adverse post-MI outcomes.

The TCS-induced pathological mechanisms and phenotypes were conserved across mouse models, neonatal rat cardiomyocytes, and human AC16 cardiomyocytes.

• Validation was performed in NRCMs (neonatal rat cardiomyocytes) under hypoxia treatment.
• Human AC16 cardiomyocytes were also used to confirm conserved mechanisms.
• Both cell models confirmed conserved phenotypes related to ferroptosis, senescence, and mitochondrial dysfunction.
• Adenoviruses, plasmids, and small-molecule inhibitors/activators were used in cellular mechanistic studies.