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

The role of mitochondria in cellular health cannot be overstated. Often referred to as the powerhouses of the cell, mitochondria are responsible for energy production, and their functionality is directly linked to cell survival and overall reproductive health. The study emphasizes how disturbances in mitochondrial dynamics can lead to detrimental metabolic consequences, contributing to conditions such as premature ovarian insufficiency. By understanding the connection between MFF and mitochondrial behavior, the researchers aim to manipulate this relationship to restore cellular balance and improve reproductive outcomes.

Recent advancements in the understanding of succinylation—one of the critical post-translational modifications of proteins—have opened new avenues in biological research. Succinylation can influence protein function, localization, and stability. The study highlights the significance of MFF succinylation within granulosa cells, the somatic cells surrounding developing ovarian follicles, which are essential for oocyte health and maturation. By selectively targeting this modification, the researchers propose a mechanism to enhance the resilience and functionality of granulosa cells, which could, in turn, ameliorate the effects of POI.

The implications of this research extend beyond the laboratory. As the global fertility crisis continues to escalate, understanding the underlying mechanisms contributing to premature ovarian insufficiency is paramount. The current treatments available for POI are limited and often involve hormone replacement therapy, which does not address the root causes. By targeting MFF succinylation, this new strategy could potentially provide a more holistic treatment option that optimizes ovarian health rather than merely managing symptoms.

To validate their hypothesis, the researchers conducted a series of meticulous in vitro and in vivo experiments aimed at analyzing the effects of MFF modulation on mitochondrial dynamics. Utilizing advanced imaging techniques, the study was able to visualize the alterations in mitochondrial morphology and function following targeted interventions. The results showcase significant improvements in mitochondrial function, protein expression, and energy metabolism within granulosa cells—an encouraging sign for the future of POI treatments.

The interplay between mitochondrial health and reproductive success is a complex relationship that offers numerous avenues for exploration. This study not only identifies MFF succinylation as a pivotal modulator of mitochondrial dynamics but also emphasizes the potential for cross-talk between metabolic pathways and reproductive physiology. As this research unfolds, there is an exciting prospect of identifying further molecular targets that could enhance fertility treatments and offer solutions for infertility associated with aging and other factors.

Moreover, the findings pave the way for the potential development of pharmacological agents that could mimic the effects of MFF succinylation modification. Through a precise understanding of the biochemical pathways involved, researchers could devise drugs that enhance mitochondrial performance and support granulosa cell function, fundamentally reshaping the therapeutic landscape of reproductive health.

While the results of this study are positive, the road ahead involves further research to translate these findings into clinical practice. Large-scale clinical trials will be necessary to assess the efficacy and safety of any potential therapeutic strategies derived from this research. Understanding the broader implications of mitochondrial health in women’s reproductive health could also lead to the development of preventative measures for women at risk of developing POI.

This research is not just a step forward for reproductive health science; it highlights the importance of metabolic regulation in the maintenance of ovarian function. As we move toward a more integrated approach to health, understanding how different biological systems interact will be crucial. The findings from this study may serve as a catalyst for an entire field of research focused on cellular metabolism, metabolic disorders, and reproductive health.

The researchers have set a new benchmark in the investigation of POI and mitochondrial dynamics, raising pivotal questions about how we understand and treat fertility issues. By drawing attention to MFF succinylation, they have opened the door to novel therapeutic strategies that may one day alleviate the burdens faced by many women experiencing premature ovarian failure.

In conclusion, this research illuminates a path forward in the quest to combat premature ovarian insufficiency. By unveiling the critical role of MFF succinylation in mitochondrial health, we are reminded of the delicate balance that sustains reproductive function. The future of ovarian health lies in our ability to harness and manipulate these biochemical pathways, offering hope not only for current patients but for future generations as well.

As this exciting field of research continues to evolve, collaboration between basic science and clinical practitioners will be essential. The real-world application of these findings has the potential to reshape the narratives surrounding fertility, offering new avenues of hope to women grappled with the challenges of early ovarian insufficiency. The rebirth of ovarian function through mitochondrial dynamics signifies a new era in reproductive health, and we stand on the brink of remarkable advancements that could change lives.

Subject of Research: Targeting MFF succinylation to restore mitochondrial dynamics in granulosa cells for premature ovarian insufficiency treatment.

Article Title: Targeting MFF succinylation: a novel therapeutic strategy for premature ovarian insufficiency by restoring mitochondrial dynamics in granulosa cells.

Article References:

Cao, Y., Tong, X., Hu, W. et al. Targeting MFF succinylation: a novel therapeutic strategy for premature ovarian insufficiency by restoring mitochondrial dynamics in granulosa cells.
J Ovarian Res (2026). https://doi.org/10.1186/s13048-026-01964-8

Image Credits: AI Generated

DOI: 10.1186/s13048-026-01964-8

Keywords: premature ovarian insufficiency, mitochondrial dynamics, MFF succinylation, granulosa cells, reproductive health, therapeutic strategy.