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Polystyrene Microplastics Induced Hepatocytes Pyroptosis, Apoptosis and Ferroptosis via GSDMD-N-Mediated
Yuelin Chen1, Meitong Liu1, Jinping Hu2
1College of Food Science and Engineering, Jilin University, Changchun, Jilin 130062, People's Republic of China.
Abstract:
Microplastics (MPs), as emerging food contaminants, have been established to exert adverse effects on the liver. However, the precise toxicological mechanisms remain elusive. Our results demonstrated that MPs triggered mitochondrial dysfunction and mitochondrial ROS (mtROS) accumulation, which subsequently activated NLRP3/caspase-1/GSDMD-N-dependent pyroptosis in hepatocytes. Notably, beyond its canonical translocation to the plasma membrane, GSDMD-N was observed to form pores on the mitochondrial outer membrane, exacerbating mitochondrial damage. The mitochondrial GSDMD-N pores amplified mtROS overproduction, triggering lysosomal membrane permeabilization (LMP) and facilitating lysosomal iron efflux, which ultimately initiated ferroptosis. Concurrently, mitochondrial GSDMD-N mediated mitochondrial intrinsic apoptosis by promoting cytochrome c release and caspase-3 activation. Collectively, our findings revealed that MPs induced GSDMD-N activation and its mitochondrial translocation, which in turn initiated pyroptosis, ferroptosis, and apoptosis in hepatocytes. This study provided novel mechanistic insights into MPs-induced hepatotoxicity, identifying GSDMD-N as a potential central hub coordinating multiple cell death modalities.
Insights
Microplastics (MPs) cause liver damage by triggering cell death pathways like pyroptosis, ferroptosis, and apoptosis. These processes are driven by mitochondrial dysfunction and the protein GSDMD-N, highlighting a novel mechanism of MP toxicity.
Area of Science:
- Environmental Toxicology
- Cellular Biology
- Hepatology
Background:
- Microplastics (MPs) are pervasive environmental contaminants with known adverse effects on liver health.
- The precise molecular mechanisms underlying MP-induced hepatotoxicity remain incompletely understood.
Purpose of the Study:
- To elucidate the toxicological mechanisms of microplastics in hepatocytes.
- To investigate the role of GSDMD-N in MP-induced cell death pathways.
Main Methods:
- Hepatocyte cell models were exposed to microplastics.
- Mitochondrial dysfunction, reactive oxygen species (ROS) production, and key proteins in pyroptosis, ferroptosis, and apoptosis pathways were analyzed.
- Cellular localization of GSDMD-N was examined.
Main Results:
- Microplastics induced mitochondrial dysfunction and mitochondrial ROS (mtROS) accumulation.
- MPs activated NLRP3/caspase-1/GSDMD-N-dependent pyroptosis.
- GSDMD-N translocated to mitochondria, exacerbating damage and initiating ferroptosis and apoptosis.
Conclusions:
- Microplastics trigger a coordinated cascade of pyroptosis, ferroptosis, and apoptosis in hepatocytes.
- GSDMD-N plays a central role in mediating these multiple cell death modalities following MP exposure.
- This study reveals novel insights into MP-induced hepatotoxicity, with GSDMD-N as a key molecular player.
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