Review Unravels Bidirectional Mitophagy-Pyroptosis Axis as Key Regulator of Cell Fate and Inflammation

Cellular inflammation and programmed cell death are critical in disease progression, yet their intricate regulatory mechanisms remain a focus of research. Pyroptosis, a highly inflammatory form of programmed cell death, is often triggered by NLRP3 inflammasome activation. Simultaneously, mitophagy, the selective degradation of damaged mitochondria, is crucial for maintaining cellular homeostasis and preventing inflammation. A deeper understanding of how these two fundamental processes interact is vital for developing novel therapeutic strategies for widespread conditions like neurodegeneration and metabolic inflammation.

This comprehensive review synthesized current scientific literature to unravel the intricate, bidirectional relationship between mitophagy and pyroptosis. The authors systematically analyzed molecular mechanisms, key signaling pathways, and the pathological implications of this axis across various organ injuries and diseases. The review aimed to identify how these processes regulate cell fate and inflammation, highlighting potential therapeutic opportunities by targeting their interplay. It examined existing evidence on how mitophagy influences pyroptosis and vice-versa, and explored the roles of specific molecular modules in modulating this axis.

The review established that mitophagy and pyroptosis form a complex, bidirectional regulatory network. Mitophagy actively suppresses NLRP3 inflammasome activation by efficiently removing damaged mitochondria, thereby reducing the release of pro-inflammatory mtROS and mtDNA, which in turn blocks pyroptosis. Conversely, pyroptosis can inhibit mitophagy through the release of inflammatory mediators and the activation of caspase-1, creating dynamic feedback loops. Key signaling modules such as PINK1/Parkin, NOD2-RIPK2, Nrf2/HO-1, and AMPK were identified as critical modulators of both mitophagy and pyroptosis. > These interactive processes are broadly implicated in determining inflammation intensity and cell survival across various organ injuries, including those affecting the brain, liver, kidney, lung, bone, and heart.