Cellular Death Switch Found: Fission Protein MFF Senses and Drives Ferroptosis

Scientists in China have uncovered a molecular control switch that sits at the heart of ferroptosis, the iron-dependent form of cell death that has captivated cancer researchers and neuroscientists alike for more than a decade. In a study published in Nature, a team led by Qiang Zhang, Fudi Wang and Junxia Min of Zhejiang University School of Medicine, together with colleagues at Zhejiang Sci-Tech University, Shanghai University of Traditional Chinese Medicine and other institutions, identifies mitochondrial fission factor, or MFF, as a protein that both senses and actively governs the ferroptotic process. The finding, published on 16 September 2026, does more than add another name to the growing list of ferroptosis regulators. It provides what the field has lacked: a unifying mechanism that connects the dynamic behaviour of membrane-bound organelles to the point of no return in oxidative cell death, along with a genetically encoded fluorescent sensor that lets researchers watch the switch flip in living cells in real time.

Ferroptosis was first described in 2012 as a form of regulated necrosis driven by iron-catalysed peroxidation of lipids in cellular membranes. Unlike apoptosis, the tidy, caspase-driven programme of cell suicide, ferroptosis is a violent affair: polyunsaturated fatty acids in membrane phospholipids are attacked by reactive oxygen species, lipid hydroperoxides accumulate, membranes rupture and the cell bursts, releasing inflammatory contents. Because tumour cells with certain metabolic vulnerabilities are exquisitely sensitive to ferroptosis, pharmacological induction of this death mode has become a major strategy in cancer drug development. Conversely, blocking ferroptosis is seen as a route to treating ischaemia-reperfusion injury, neurodegeneration and fatty liver disease. Yet despite an explosion of knowledge about the lipid chemistry and the key defence enzymes such as GPX4 and FSP1, the field has struggled to explain how the cell’s organelles coordinate their behaviour during the death process, and how a cell decides, at the level of organelle dynamics, that ferroptosis is under way.

To find that missing link, the team turned to quantitative phosphoproteomics, a mass-spectrometry technique that measures the attachment of phosphate groups to thousands of proteins simultaneously. Because phosphorylation is the cell’s fastest and most reversible regulatory currency, comparing phosphorylation patterns across different forms of cell death should reveal the specific molecular events that distinguish ferroptosis from apoptosis and necroptosis. The researchers treated cells with inducers of each death modality, including the GPX4 inhibitor RSL3 and the system-xc-blocker erastin for ferroptosis, staurosporine for apoptosis, and TNF-related cocktails for necroptosis, and then systematically compared the resulting phosphoproteomes. Using weighted gene co-expression network analysis, they identified a module of phosphorylation changes uniquely associated with ferroptosis, and one protein stood out: MFF, a tail-anchored outer-membrane protein already known to serve as the docking platform for the fission machinery of both mitochondria and peroxisomes.

MFF was an intriguing candidate for reasons that go beyond its phosphorylation behaviour. Since its identification in 2008, MFF has been recognized as the receptor on the mitochondrial and peroxisomal surface that recruits the dynamin-related protein DRP1, the engine that constricts and severs these organelles. Mitochondria had long been suspected of participating in ferroptosis, with fragmented morphology and loss of membrane potential reported in dying cells, and peroxisomes had recently been implicated as factories for the ether-linked phospholipids that serve as preferred substrates for peroxidation. But whether organelle fragmentation was a cause or a consequence of ferroptotic death remained contested. The new data settle the question in a striking way: deleting MFF renders cells resistant to ferroptosis across multiple inducers and cell lines, including HeLa, HT-1080, SH-SY5Y, HepG2 and A549 cells, without affecting their sensitivity to apoptosis or necroptosis, while restoring MFF re-sensitizes them. Ferroptotic stress triggers MFF-dependent fragmentation and dysfunction of both mitochondria and peroxisomes, and this remodelling amplifies reactive oxygen species production in both compartments.

The team then traced the biochemical signal that switches MFF on. Through untargeted metabolomics and eicosanoid profiling, they identified 17-hydroxyeicosatetraenoic acid, or 17-HETE, a lipid mediator produced by the cytochrome P450 enzyme CYP4A11, as the molecule that accumulates during ferroptosis and promotes phosphorylation of MFF at a specific amino acid, serine 155. When the researchers mutated this serine to a non-phosphorylatable alanine, cells became resistant to ferroptotic organelle fragmentation and death; a phosphomimetic aspartate substitution had the opposite effect. Crucially, the Ser155 phosphorylation event was detected during ferroptosis but not during apoptosis or necroptosis, and it also appeared in mouse models of cardiac ischaemia-reperfusion injury and diet-induced fatty liver disease, two pathologies in which ferroptosis is strongly implicated. This makes phospho-Ser155 MFF what the authors call a specific sensor of the ferroptotic state, a single chemical mark that reports on the death programme with high selectivity.

Watching a single phosphorylation event in living cells is technically demanding, so the team engineered a solution. They built MFF-SPARK, a biosensor based on SPARK, a phase-separation-based kinase reporter platform developed by the same group in 2018. The design couples the MFF sequence surrounding Ser155 to a phosphoserine-binding domain and fluorescent modules that coalesce into bright droplets only when the site is phosphorylated. In cells undergoing ferroptosis, the sensor lights up within minutes of drug addition, and it responds to a panel of ferroptosis inducers, including RSL3, ML162, erastin, FINO2 and iron overload, while remaining dark during apoptosis and necroptosis. The sensor worked across HeLa, HEK293T, HepG2 and U-2 OS cells and in genetically modified backgrounds lacking GPX4, confirming that it reports the endogenous ferroptosis programme rather than an artefact of any single drug.

With a real-time readout in hand, the researchers could do what had previously been impossible: screen for the enzymes that write and erase the phospho-Ser155 mark as ferroptosis unfolds. The screen revealed a coordinated kinase-phosphatase pair. Protein kinase C beta, PKCβ, phosphorylates MFF at Ser155 during ferroptosis; genetic or pharmacological inhibition of PKCβ reduces MFF phosphorylation, lipid peroxidation and cell death, and the effect requires the presence of MFF with an intact Ser155. On the opposing side, the phosphatase DUSP22, which physically interacts with MFF, removes the phosphate and restrains ferroptosis; deleting DUSP22 increases both lipid peroxidation and death in an MFF- and Ser155-dependent manner. The pair establishes a reversible rheostat on the ferroptosis pathway, and the SPARK sensor allowed the authors to visualize the balance tipping toward phosphorylation as cells commit to death.

The mechanistic picture that emerges is one of coordinated organelle conspiracy. Phosphorylated MFF drives simultaneous fission of mitochondria and peroxisomes, intensifying the metabolic crosstalk between them. Peroxisomal remodelling engages PPARα-mediated transcriptional control of β-oxidation enzymes such as ACOX1 and catalase, shifting the peroxisomal redox balance, while mitochondrial fragmentation promotes release of mitochondrial DNA into the cytosol through VDAC1 oligomer-formed pores, feeding inflammatory signalling pathways. The lipid mediator 17-HETE, generated by CYP4A11, feeds forward to sustain MFF phosphorylation, creating a self-amplifying loop in which organelle dysfunction, oxidative stress and lipid peroxidation reinforce one another until the cell dies. This interorganelle amplification model explains why ferroptosis, once triggered, proceeds so explosively compared with other death modalities.

The translational payoff came from a screen for pharmacological activators of the PKCβ-MFF axis. The team identified avermectin B1, a compound best known from the antiparasitic drug family that includes ivermectin, as an activator that promotes MFF Ser155 phosphorylation, drives mitochondrial and peroxisomal fission in an MFF-dependent fashion and sensitizes tumour cells to ferroptosis inducers such as RSL3. In xenograft experiments with HCT-116 colorectal cancer cells in mice, combining avermectin B1 with a ferroptosis inducer suppressed tumour growth more effectively than either agent alone, and the combination was tolerated, with body weight, organ weights, serum biochemistry and histopathology showing no major toxicity in treated mice. The effect required both PKCβ and MFF, confirming that the compound works through the newly defined axis rather than an unrelated pathway.

For the ferroptosis field, the study delivers three things at once: a mechanistic node, a monitoring tool and a drug lead. MFF phosphorylation at Ser155 now stands as a central regulatory point where lipid signals, kinase-phosphatase dynamics and organelle architecture converge to execute iron-dependent death. MFF-SPARK offers researchers a way to quantify ferroptosis in living cells and, potentially, in vivo, replacing endpoint assays of lipid peroxidation with real-time kinetic measurements. And the demonstration that an approved-drug-family compound can flip the switch in tumours suggests that sensitizing cancers to ferroptosis by targeting organelle fission is a pharmacologically tractable strategy. Whether the same axis can be dampened to protect the heart and liver from ferroptotic injury, and whether MFF phosphorylation status can serve as a biomarker to predict which patients will respond to ferroptosis-inducing therapies, are questions the Zhejiang-led team and others will now be racing to answer.

Subject of Research: The role of mitochondrial fission factor phosphorylation in regulating ferroptotic cell death and organelle remodelling

Article Title: Mitochondrial fission factor senses and governs ferroptosis

Article References: Dai, S., Dai, X., Zhang, T., Qi, Y., Yang, X., Diao, P., Ge, C., Huang, W., Ran, J., Yang, X., Zhang, P., Zheng, K., Wang, R., Qian, H., Zhang, K., Wu, J., Fu, C., Ba, Q., Min, J., … Zhang, Q. (2026). Mitochondrial fission factor senses and governs ferroptosis. Nature. https://doi.org/10.1038/s41586-026-11020-6

Image Credits: AI Generated

DOI: 10.1038/s41586-026-11020-6

Keywords: ferroptosis, mitochondrial fission factor, MFF, phosphorylation, 17-HETE, PKCβ, DUSP22, peroxisomes, lipid peroxidation, avermectin B1, biosensor, cancer therapy