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Caspase-Independent programmed cell death is not necessarily necroptosis

Open AccessPublished:April 23, 2022DOI:https://doi.org/10.1016/j.xjon.2022.04.034
      To the Editor:
      The authors reported no conflicts of interest.
      The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.
      How to regulate cell death has always been an important means for people to intervene in the development of disease and improve prognosis. With the development of research, the mechanism of caspase-independent programmed cell death has been improved continuously, including the necroptosis and the ferroptosis, which is defined as a mode of caspase-independent regulated necrosis that is dramatically characterized by iron-dependent lipid peroxide accumulation.
      • Lou J.
      • Zhou Y.
      • Feng Z.
      • Ma M.
      • Yao Y.
      • Wang Y.
      • et al.
      Caspase-independent regulated necrosis pathways as potential targets in cancer management.
      It is reported that ferroptosis is governed by 3 antioxidant axes, ie, the cyst(e)ine/GSH/GPX4 axis, the GCH1/BH4/DHFR axis, and the FSP1/CoQ10 axis, all of which are fueled by nicotinamide adenine dinucleotide phosphate.
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      • Conrad M.
      The metabolic underpinnings of ferroptosis.
      Ueda and colleagues from Kyoto University considered that terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive and caspase-3–negative cells were counted as necroptotic cells, and TUNEL-positive and caspase-3–positive were counted as apoptotic cells in immunofluorescence.
      • Ueda S.
      • Chen-Yoshikawa T.F.
      • Tanaka S.
      • Yamada Y.
      • Nakajima D.
      • Ohsumi A.
      • et al.
      Protective effect of necrosulfonamide on rat pulmonary ischemia-reperfusion injury via inhibition of necroptosis.
      However, the caspase-independent cell death form is not only necroptosis. That is to say TUNEL-positive and caspase-3–negative cells also possibly include ferroptotic cells and other caspase-independent cells that have not been reported. This approach is not rigorous and needs to be improved.

      References

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        Protective effect of necrosulfonamide on rat pulmonary ischemia-reperfusion injury via inhibition of necroptosis.
        J Thorac Cardiovasc Surg. 2022; 163: e113-e122

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      • Reply From Authors: How a cell dies matters and how to evaluate it also matters
        JTCVS OpenVol. 11
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          This study aimed to investigate the effect of necrosulfonamide (NSA), a mixed-lineage kinase domain-like protein (MLKL) inhibitor, on pulmonary ischemia-reperfusion injury (IRI) in a simple and validated in vivo model. NSA treatment showed a protective effect on pulmonary IRI, because of improvement of physiological parameters and histological findings and a lower level of proinflammatory cytokines were observed in the NSA-treated group.1
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