Therapeutic potential of PANoptosis in calcium oxalate crystal-induced kidney injury: An integrated view of cell death pathways.

Calcium oxalate (CaOx) stones account for more than 80% of kidney stones and are one of the most common diseases in the urinary system. The core pathological event of CaOx crystals is the damage of renal tubular epithelial cells (RTECs). Recent studies have shown that CaOx crystals can induce a variety of programmed cell death (PCD) pathways, such as apoptosis, pyroptosis, necroptosis, and ferroptosis, in RTECs at the same time, and there are complex compensations and crosstalk between these death pathways, resulting in the limited efficacy of a single targeting strategy. Therefore, exploring the mechanisms that can integrate the regulation of multiple cell death pathways has become an important direction in this field. PANoptosis is an inflammatory PCD mode driven by the PANoptosome complex, which synchronously triggers the characteristic events of three death pathways in the same cell through the cooperative integration of the core molecular components of pyroptosis, apoptosis, and necroptosis. In this process, cysteinyl aspartate-specific proteinase-8 (Caspase-8) and receptor-interacting serine/threonine kinase 3 (RIPK3), as the core components of the PANoptosome, jointly determine whether the cell goes to a single programmed death or an integrated PANoptosis. The limited studies' evidence supports that CaOx crystals induce concurrent activation of apoptosis, pyroptosis, and necroptosis, suggesting the possibility of PANoptosis in CaOx‑induced kidney injury. At the same time, the rupture of the cell membrane caused by PANoptosis, similar to other forms of PCD, releases a large number of damage-associated molecular patterns (DAMPs), which activate innate immunity to form an inflammatory cascade and further aggravates tissue damage. PANoptosis, with multi-target characteristics, provides a new idea to overcome the bottleneck of single-target strategy for CaOx-induced kidney injury. In the future, new biomarkers and multi-target intervention strategies should be developed based on PANoptosis, which is expected to open up a new path for the prevention and treatment of CaOx-induced kidney injury.