The known forms of cell death have expanded from two, apoptosis and necrosis, to more than twenty distinct mechanisms, most of them discovered in the last 27 years
The known forms of cell death have expanded from two, apoptosis and necrosis, to more than twenty distinct mechanisms, most of them discovered in the last 27 years
Each cell death pathway serves a specific purpose: one raises an alarm for the immune system, another passes unnoticed, and sometimes a cell that has already begun to die comes back to life. New pathways are found almost every year: at least four in 2025, and one more this spring.
For a long time, cell death was divided into two categories: disorderly necrosis, in which a cell is crushed, cut, or poisoned and falls apart without any programme, and regulated apoptosis, in which the cell dismantles itself into membrane-wrapped vesicles that the immune system clears away. This dichotomy held until new tools (gene editing, high-resolution microscopy, methods for profiling thousands of molecules at once) began to reveal death pathways that did not fit either category. A Nature article published on 22 September brings them together: since 1999, researchers have described roughly twenty new mechanisms, and the list continues to grow.
The cell biologist Daolin Tang was screening compounds to kill cancer cells and kept encountering unexplained death, until he discovered that pH in those cells had spiked sharply: they became too alkaline and died from it. Tang named the finding alkaliptosis.
"Cell death is not simply the end of a cell's life"
The list includes pyroptosis and necroptosis (explosive, proinflammatory forms), ferroptosis (driven by iron accumulation that destroys cell membranes), cuproptosis (from copper overload), and a sodium-overload form of death described only in 2025. This spring, researchers studying flatworms identified yet another pathway: exploding cells called "ruptoblasts" that spray toxins onto bacteria.
The mode of death determines what happens to the surrounding tissue afterward. The biophysicist Ana García-Sáez explains why so many different pathways coexist: if a pathogen blocks one death programme, the infected cell needs a backup. "It is like a race against the pathogen," she says. In some cells, death unfolds in several stages, resembling a checklist before departure: intestinal cells infected with Salmonella use an enzyme that patches holes in their own membrane so they can leave the gut lining neatly, without triggering excessive inflammation.
The most unexpected finding is that death is sometimes reversible. In 2007, in Hong Kong, the cell biologist Ho Lam Tang and his sister, the tumour biologist Ho Man Tang, noticed tiny cells in Petri dishes that had survived apoptosis: once the substance that triggered their death was washed away, the cells recovered by the following morning. The phenomenon was named anastasis, "rising from the dead." Eleven journals rejected the paper before video footage of the reviving cells persuaded Molecular Biology of the Cell to publish it in 2012. Since then, reversibility has also been observed in ferroptosis and necroptosis, pushing the point of no return much further than previously assumed. According to a hypothesis by García-Sáez and the immunologist Petr Bhrozh (University of Lausanne), that point is the irreversible destruction of mitochondrial membranes.
Senescent cells, which accumulate in tissues with age, are notable for their resistance to apoptosis: they cling to life through BCL-2 proteins that block their own death programme. Senolytic drugs are designed to break down precisely this defence and force senescent cells to finally die. Breaking it, however, is not the only option: in 2024 mouse experiments, lipid senolytics killed such cells by bypassing the BCL-2 shield altogether, triggering ferroptosis instead of dismantling it. Each death pathway, it turns out, has its own lever.