Molecular mechanisms of regulated necrosis

Semin Cell Dev Biol. 2014 Nov;35:24-32. doi: 10.1016/j.semcdb.2014.02.006. Epub 2014 Feb 26.


It is now clear that apoptosis does not constitute the sole genetically encoded form of cell death. Rather, cells can spontaneously undertake or exogenously be driven into a cell death subroutine that manifests with necrotic features, yet can be inhibited by pharmacological and genetic interventions. As regulated necrosis (RN) plays a major role in both physiological scenarios (e.g., embryonic development) and pathological settings (e.g., ischemic disorders), consistent efforts have been made throughout the last decade toward the characterization of the molecular mechanisms that underlie this cell death modality. Contrarily to initial beliefs, RN does not invariably result from the activation of a receptor interacting protein kinase 3 (RIPK3)-dependent signaling pathway, but may be ignited by distinct molecular networks. Nowadays, various types of RN have been characterized, including (but not limited to) necroptosis, mitochondrial permeability transition (MPT)-dependent RN and parthanatos. Of note, the inhibition of only one of these modules generally exerts limited cytoprotective effects in vivo, underscoring the degree of interconnectivity that characterizes RN. Here, we review the signaling pathways, pathophysiological relevance and therapeutic implications of the major molecular cascades that underlie RN.

Keywords: AIF; Entosis; Ferroptosis; Mitochondrial membrane permeabilization; Pyroptosis; RIPK3.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Caspase 8 / metabolism
  • Fas-Associated Death Domain Protein / metabolism
  • Humans
  • Membrane Potential, Mitochondrial / physiology*
  • Models, Biological*
  • Necrosis / metabolism
  • Necrosis / physiopathology*
  • Protein Kinases / metabolism
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Signal Transduction / physiology*


  • FADD protein, human
  • Fas-Associated Death Domain Protein
  • MLKL protein, human
  • Protein Kinases
  • RIPK1 protein, human
  • RIPK3 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Caspase 8