bims-cediti 2025-12-21 papers

bims-cediti

Biomed News

on Cell death in innate immunity, inflammation, and tissue repair

Issue of 2025–12–21
fourteen papers selected by
Kateryna Shkarina, Universität Bonn

Inflammation and cell death drive Monkeypox-induced viral pathogenesis.
Resident phagocytes promote non-cell-autonomous fragmentation of apoptotic cells.
SARM1 as a dsDNA detector to sense nuclear damage and viruses to drive cell death.
Mammary Fibroblasts Secrete Damage Associated Molecular Patterns through Extracellular Vesicles in Response to Ionizing Radiation.
IFNγ priming enables NLRP3 inflammasome activation in human keratinocytes in vitro.
Caspase-1 Dependent Neutrophil Pyroptosis Contributes to Fine Particulate Matter-Induced Lung Inflammation.
Lack of caspase 8 directs neuronal progenitor-like reprogramming and small cell lung cancer progression.
Diurnally-Regulated Corticosterone and Melatonin Inversely Control Endotoxin-Induced Acute Immune Responses.
Gasdermin B-mediated pyroptosis as a host defense against swine enteric coronaviruses and its antagonism by PEDV.
Polystyrene microplastics cross the murine intestine and induce inflammatory cell death after phagocytosis by human monocytes and neutrophils.
α-hemolysin polymorphisms in methicillin-resistant Staphylococcus aureus clinical isolates regulate ADAM10-dependent neutrophil IL-1β secretion.
Mitochondrial RNA cytosolic leakage drives the SASP.
Hyperactive Rac converts sublethal nibbling to lethal phagocytosis in vivo.
Ferroptosis inhibition protects against α-synuclein-related neuronal cell death.

Cell Mol Immunol. 2025 Dec 16.

Inflammation and cell death drive Monkeypox-induced viral pathogenesis.

Harrison Bazley, Abhimanu Pandey, Si Ming Man.

DOI: https://doi.org/10.1038/s41423-025-01379-3
Sci Adv. 2025 Dec 19. 11(51): eadz5264

Resident phagocytes promote non-cell-autonomous fragmentation of apoptotic cells.

Jascinta P Santavanond, Georgia K Atkin-Smith, Irene Lozano-González, Joan Roncero-Carol, Lanzhou Jiang, Amy L Hodge, Dilara C Ozkocak, Kelin Zhao, Daniel H D Gray, Marco J Herold, Andrew J Kueh, Gemma F Ryan, Rochelle Tixeira, Michael F Olson, Mark D Hulett, Amy A Baxter, Ivan K H Poon, Esteban Hoijman.

Phagocytosis of apoptotic cells maintains tissue homeostasis and regulates inflammation. A proposed facilitator of apoptotic cell clearance is the fragmentation of these cells into apoptotic bodies (ApoBDs) through cell-autonomous processes involving caspases and cytoskeletal rearrangement. Although this fragmentation process is considered a hallmark of apoptosis, its progression in tissue environments remains underexplored. Here, we examine the in vivo apoptotic dynamics of mouse thymocytes and pluripotent cells from zebrafish embryos. We show that the in vivo biogenesis of ApoBDs is independent of known cell-intrinsic regulators. Instead, fragmentation depends on actin-rich protrusions from neighboring resident phagocytes, which mechanically compress apoptotic cells to break them into smaller particles. Four-dimensional in vivo tracking of apoptotic cells reveals that both phagocyte-mediated fragmentation and phagocytosis are size sensitive, indicating that apoptotic size reduction mediated by phagocytes enhances their own clearance abilities. This non-cell-autonomous fragmentation ensures rapid apoptotic cell clearance, crucial for maintaining tissue homeostasis in physiological settings.

DOI: https://doi.org/10.1126/sciadv.adz5264
Mol Cell. 2025 Dec 18. pii: S1097-2765(25)00944-X. [Epub ahead of print]85(24): 4487-4489

SARM1 as a dsDNA detector to sense nuclear damage and viruses to drive cell death.

Adel Avetisyan, Ernesto Manzo, Marc R Freeman.

In a recent issue of Cell, Wang et al.1 found that the pro-degenerative NAD+ hydrolase SARM1 can bind and be activated by dsDNA. This expands potential roles for SARM1 to sensing DNA damage or viruses and activating cell death.

DOI: https://doi.org/10.1016/j.molcel.2025.11.027
bioRxiv. 2025 Nov 28. pii: 2025.11.25.690532. [Epub ahead of print]

Mammary Fibroblasts Secrete Damage Associated Molecular Patterns through Extracellular Vesicles in Response to Ionizing Radiation.

Greg Berumen Sánchez, Purvi Patel, Preston Gomez-Crase, Chloe Kim, Kristie Lindsey Rose, Marjan Rafat.

Ionizing radiation (IR) is an integral component of cancer therapy. Cellular exposure to IR typically leads to major biological consequences including cell death and senescence. Furthermore, tissue injury in known to involve the release of damage-associated molecular patterns (DAMPs) into the extracellular space, which trigger inflammation and wound healing. However, DAMP release in the context of radiation injury remains to be fully characterized. Evidence suggests that extracellular vesicle (EV) secretion and associated cargo components are part of the cellular response to IR, but the mechanisms integrating cellular damage and EV secretion post-IR are largely unexplored. In this study, we show that acute IR-induced damage in mammary fibroblasts results in a senescence-like phenotype and substantially increased EV secretion. Quantitative proteomic analysis revealed that IR-induced EVs are enriched with extracellular and intracellular DAMPs, along with other pro-inflammatory mediators. We show that knockdown of the GTPase Rab27a abrogates IR-induced EV secretion and inhibits the enrichment of key DAMPs in EVs. By examining the integration of cellular damage and senescence with the release of inflammatory signals, this study elucidates a potentially critical role for EV-associated proteins in the radiation response.

DOI: https://doi.org/10.1101/2025.11.25.690532
J Invest Dermatol. 2025 Dec 11. pii: S0022-202X(25)03630-9. [Epub ahead of print]

IFNγ priming enables NLRP3 inflammasome activation in human keratinocytes in vitro.

Pritisha Rozario, Ying Shiang Lim, Suet Lee Shirley Ding, Muhammad Jasrie Firdaus, Stephen Wearne, Han Siang Brandon Wong, Rae Chua, Kim Samirah Robinson, Tung Sem Julie Chu, Meng Liu, Shan Sophie Carrie Cai, Sern Ting Eugene Tan, Soon Keong Wee, Mart Matthias Lamers, Navin Kumar Verma, Yun Xia, Peng Huat Eric Yap, John Edmund Armourer Common, Franklin Zhong.

  While NLRP3 has been extensively studied in myeloid cells, its existence and regulation in epithelial cells, including keratinocytes, are unclear. In fact, whether human keratinocytes express a functional NLRP3 inflammasome at all remains a matter of debate in the inflammasome field. Here, we provide additional evidence that NLRP3 is repressed in human keratinocytes cultured under non-inflammatory conditions but can be sharply induced by interferon-γ (IFNγ)-but not lipopolysaccharide (LPS). In this IFNγ-primed state, not all established NLRP3 activators are specific to NLRP3. We report that nigericin-driven keratinocyte pyroptosis occurs via both NLRP1 and NLRP3, whereas Staphylococcus aureus α-hemolysin (Hla) exclusively and nonredundantly activates NLRP3, even though both require K+ efflux. Furthermore, in the presence of T cells, certain virulent S. aureus strains can cause NLRP3-dependent pyroptotic death in keratinocytes in vitro through the cooperative actions of superantigens (SAgs) and Hla. In summary, our findings establish the strict inducibility and functional relevance of the NLRP3 inflammasome in non-myeloid, epithelial cells in vitro. These results resolve conflicting reports and position keratinocytes as a context-specific, non-hematopoietic cellular model for studying NLRP3 activation in host-microbe interactions at barrier tissues.

Keywords:  NLRP1; NLRP3; S. aureus; inflammasome

DOI:  https://doi.org/10.1016/j.jid.2025.11.019
J Biochem Mol Toxicol. 2025 Dec;39(12): e70639

Caspase-1 Dependent Neutrophil Pyroptosis Contributes to Fine Particulate Matter-Induced Lung Inflammation.

Jia Mai, Shenshen Zhu, Zhaoke Wu, Peiyu Zhu, Yujie Li, Weidong Wu, Junxi Zhang, Yuefei Jin, Yacong Bo.

  As a pollutant, Fine particulate matter (PM2.5) directly deposits in alveoli to induce lung inflammation, yet its pathogenic mechanism remains unclear. PM2.5-induced pulmonary inflammation will trigger the activation of Caspase-1 (Casp1). We seek to elucidate the role of pyroptosis in PM2.5-induced lung inflammation by employing Casp1 knock-out (KO) mice and a specific pyroptosis inhibitor (Disulfiram, DSF). We found the typical pathological changes were comparatively alleviated in the Casp1 KO mice. Notably, in Casp1 KO mice, there was a significant downregulation of gasdermin D (GSDMD) and GSDMD-N at the protein levels. The Casp1 KO mice exhibited a decrease in the numbers of pyroptotic neutrophils. After administrating with DSF, we observed the downregulation of GSDMD and GSDMD-N, along with a decreased number of pyroptotic neutrophils. These findings suggest that neutrophils contribute to PM2.5-induced lung inflammation depending on Caspase-1/pyroptosis signaling pathway. These results demonstrate that PM2.5 triggers lung inflammation via the neutrophil Caspase-1/pyroptosis pathway, revealing a novel mechanism of PM2.5-mediated inflammation and suggesting DSF as a potential therapeutic agent for PM2.5-induced pneumonia.

Keywords:  Caspase‐1; PM2.5; lung inflammation; neutrophil; pyroptosis

DOI:  https://doi.org/10.1002/jbt.70639
Nat Commun. 2025 Dec 18. 16(1): 11280

Lack of caspase 8 directs neuronal progenitor-like reprogramming and small cell lung cancer progression.

Ariadne Androulidaki, Fanyu Liu, Christina M Bebber, Ilmars Kisis, Vignesh Sakthivelu, Pascal Hunold, Lioba Koerner, Alina Dahlhaus, Fatma Isil Yapici, Christina Grimm, Alicja Pacholewska, Sofya Tishina, Franka Doskotz, Lucia A Torres Fernández, Jenny Stroh, Ali T Abdallah, Julia Beck, Lejla Mulalic, Anna Schmitt, Holger Grüll, Thorsten Persigehl, Alexander Quaas, Martin Peifer, Johannes Brägelmann, H Christian Reinhardt, Pascal Nieper, Robert Hänsel-Hertsch, Roman K Thomas, Julie George, Michal R Schweiger, Manolis Pasparakis, Filippo Beleggia, Silvia von Karstedt.

Most neuroendocrine cancers lack caspase 8 protein expression. While this feature was thought to facilitate escape from extrinsic apoptosis, its cancer-regulatory function has remained unexplored. Here, we devise a mouse model of small cell lung cancer (SCLC) recapitulating the lack of expression of caspase 8 seen in humans and uncover an unexpected role for necroptosis-fueled pre-tumoral inflammation resulting in reprogramming towards a neuronal progenitor cell-like state and increased metastatic disease. Notably, transcriptional signatures of this cellular state are enriched in relapsed and metastatic human SCLC. Mechanistically, caspase 8 loss within the pre-tumoral niche promotes inflammation marked by increased recruitment of regulatory T cells (Tregs) which are responsible for the promotion of metastatic disease. Importantly, inactivation of the necroptosis executioner MLKL reverses pre-tumoral inflammation, decreases metastasis as well as neuronal-like reprogramming. Taken together, our findings suggest that pre-tumoral inflammatory cell death contributes to neuronal progenitor mimicry, immunosuppression and increased metastasis in SCLC.

DOI: https://doi.org/10.1038/s41467-025-67142-4
Eur J Immunol. 2025 Nov;55(11): e70077

Diurnally-Regulated Corticosterone and Melatonin Inversely Control Endotoxin-Induced Acute Immune Responses.

Montaser Haddad, Sebastien Trzebanski, Ramon Bossardi Ramos, Lizeth-Alejandra Ordonez Moreno, Allison Rahtes, Eman Khatib-Massalha, Priyasmita Chakrabarti, Ekaterina Petrovich-Kopitman, Noa Wigoda, Adi Biram, Wolfram C Poller, Alejandra Aroca-Crevillén, Andrés Hidalgo, Gabrielle Fredman, Filip K Swirski, Mikala Egeblad, Regina P Markus, Martin Schlegel, Steffen Jung, Tsvee Lapidot, Jose M Adrover, Orit Kollet.

  The timing of endotoxin administration in mice matters and is associated with diurnal variation in survival; however, underlying mechanisms remain poorly understood. Here, we report that afternoon LPS challenges in mice induce a robust inflammatory response involving increased neutrophil activation and release of cytotoxic mediators, causing higher mortality compared with challenges at midnight. Mechanistically, the cyclic patterns of corticosterone and melatonin hormones differentially modulate neutrophil responses. The afternoon corticosterone peak was associated with heightened incidence and severity of LPS-induced hyperinflammation. Conversely, higher melatonin levels at midnight conferred protection to challenged mice by restraining the magnitude of inflammation. High cortisol and low melatonin profiles detected in septic patients mirror those observed in mice and suggest a novel prognostic marker for sepsis. Our study unveils a regulatory network that links light/dark signals and circadian-regulated hormones to the intensity of the host's inflammatory response to infection.

Keywords:  corticosterone; inflammation; melatonin; neutrophils

DOI:  https://doi.org/10.1002/eji.70077
mBio. 2025 Dec 18. e0290425

Gasdermin B-mediated pyroptosis as a host defense against swine enteric coronaviruses and its antagonism by PEDV.

Yao Yao, Ning Huang, Xinyu Huang, Mengqi Yuan, Li Kang, Yanlong Ma, Jun Han, Guozhong Zhang, Pinghuang Liu.

  Gasdermin B (GSDMB), a member of the spore-forming protein gasdermin (GSDM) family, is critical for inflammation and immunity and has been genetically linked to human diseases. Despite its prominent expression at mucosal surfaces, including the gastrointestinal and respiratory tracts, GSDMB's role in defending against viral pathogens at these barrier tissues remains poorly defined. Here, we reveal that porcine GSDMB (pGSDMB), which is highly expressed in the intestinal epithelium, is a potent innate restriction factor against porcine epidemic diarrhea virus (PEDV), a major enteric coronavirus. Mechanistically, PEDV infection activated caspase-3/6/7 to cleave pGSDMB at D237, generating an active N-terminal fragment (pGSDMB1-237) that triggered pyroptotic cell death to limit viral propagation. Conversely, PEDV evolved a sophisticated countermeasure: the viral nonstructural proteins nsp1 and nsp15 cooperatively suppressed pGSDMB protein expression. This immune evasion required a critical region within nsp1 (86-110 amino acids) and the catalytic endoribonuclease residues (H226 and H241) of nsp15. Importantly, pGSDMB-mediated pyroptosis broadly inhibited replication of diverse swine enteric coronaviruses, including transmissible gastroenteritis virus and porcine deltacoronavirus. Our findings establish GSDMB as an executor of pyroptosis that guards the mucosal interface against coronavirus infection and unveils a novel viral strategy to circumvent this defense, highlighting new avenues for therapeutic intervention against coronaviruses.IMPORTANCEWhile gasdermin B (GSDMB) is genetically associated with mucosal inflammatory diseases like asthma, its function in host defense at mucosal barriers remains an open question. This study defines a critical role for GSDMB as a central innate immune executor against enteric coronaviruses. We demonstrate that porcine GSDMB (pGSDMB) is cleaved during infection to trigger pyroptotic cell death, thereby restricting the replication of porcine epidemic diarrhea virus (PEDV) and other swine enteric coronaviruses. Furthermore, we identify a novel immune evasion strategy whereby PEDV employs its nsp1 and nsp15 proteins to suppress pGSDMB expression, delineating the key viral domains required for this countermeasure. These findings bridge a significant knowledge gap by revealing GSDMB as a guardian of the mucosal interface and inform the development of potential broad-acting therapeutic strategies against coronaviruses.

Keywords:  caspases; coronaviruses; gasdermin B; porcine epidemic diarrhea virus (PEDV); pyroptosis

DOI:  https://doi.org/10.1128/mbio.02904-25
iScience. 2025 Dec 19. 28(12): 114076

Polystyrene microplastics cross the murine intestine and induce inflammatory cell death after phagocytosis by human monocytes and neutrophils.

Giulio Giustarini, Tim L P Skrabanja, Annemijne E T van den Berg, Selma van Staveren, Tom Vos, Zhi Hui Zhou, Thomas Klaessens, Eva Mulder, Joëlle Klazen, Joost Smit, Raymond Pieters, Leo Koenderman, Nienke Vrisekoop.

  Microplastics have been detected in human blood, raising concerns about human health. Here, we investigated the tissue distribution of microplastics after oral exposure in mice and their effects on mouse and human phagocytes. Both 1 and 10 μm polystyrene (PS) particles crossed the intestinal epithelium and were detected in the blood and liver of mice after ten days of oral administration. Intravital microscopy visualized in vivo phagocytosis of 1 μm PS by mouse neutrophils in the liver. Phagocytosis by human neutrophils required plasma or serum-coating of PS and was complement-dependent. Phagocytosis of coated PS induced monocyte and neutrophil cell death, with 10 μm PS requiring a single particle uptake, whereas 1 μm PS required much higher exposure levels. Neutrophil cell death upon 10 μm PS phagocytosis was characterized by extracellular DNA and classified as NETosis. These findings demonstrate that microplastics can penetrate tissues and provoke pro-inflammatory immune cell death, suggesting potential risks to human health.

Keywords:  Biological sciences; Cell biology; Health sciences; Molecular biology experimental approach

DOI:  https://doi.org/10.1016/j.isci.2025.114076
bioRxiv. 2025 Dec 14. pii: 2025.12.13.694139. [Epub ahead of print]

α-hemolysin polymorphisms in methicillin-resistant Staphylococcus aureus clinical isolates regulate ADAM10-dependent neutrophil IL-1β secretion.

Karl Liboro, Jolynn T Chau, James D Begando, Serena Abbondante, Angela Lackner, Yan Sun, Michaela E Marshall, Nghi Ly, Victor D Johnson, George R Dubyak, Michael Gilmore, Reginald McNulty, Camille Andre, Eric Pearlman.

Staphylococcus aureus α-hemolysin (Hla) is a major virulence factor that utilizes cell surface ADAM10 to oligomerize and form a functional heptameric pore. We show here that Hla from strain USA300 is required to induce IL-1β secretion by neutrophils and to cause severe corneal disease in mice. We also demonstrate that in contrast to USA300 and other clonal complex 8 (CC8) methicillin resistant S. aureus (MRSA) isolated from the skin, CC5 Hla from corneas of infected patients have single nucleotide polymorphisms (SNP) that result in two amino acid substitutions, D208E (Asp-Glu) and I275T (Ile-Thr). Structural modeling predicts CC5 Hla self-assembly and altered binding to ADAM10 that is distinct from CC8 Hla. The ADAM10 inhibitor GI254023X blocked neutrophil IL-1β secretion induced by Hla-expressing CC8, but not by CC5 conditioned media, indicating that these Hla polymorphisms play an important role in Hla receptor binding and neutrophil IL-1β secretion, and affect corneal disease severity.

DOI: https://doi.org/10.64898/2025.12.13.694139
Nat Commun. 2025 Dec 15. 16(1): 10992

Mitochondrial RNA cytosolic leakage drives the SASP.

Stella Victorelli, Madeline Eppard, Hélène Martini, Seung-Hwa Woo, Stacia P A Everts, Gung Lee, Nicholas Pirius, Nuan Han, Eugene Y Liang, Ana Catarina Franco, Yeaeun Han, Dominik Saul, Eva Nóvoa, Rubén Nogueiras, Patrick L Splinter, Steven P O'Hara, Olivia Morgenthaler, Lucía Valenzuela-Pérez, Hyun Se Kim Lee, Diana Jurk, Nicholas F LaRusso, Petra Hirsova, João F Passos.

Senescent cells secrete proinflammatory factors known as the senescence-associated secretory phenotype (SASP), contributing to tissue dysfunction and aging. Mitochondrial dysfunction is a key feature of senescence, influencing SASP via mitochondrial DNA (mtDNA) release and cGAS/STING pathway activation. Here, we demonstrate that mitochondrial RNA (mtRNA) also accumulates in the cytosol of senescent cells, activating RNA sensors RIG-I and MDA5, leading to MAVS aggregation and SASP induction. Inhibition of these RNA sensors significantly reduces SASP factors. Furthermore, BAX and BAK play a key role in mtRNA leakage during senescence, and their deletion diminishes SASP expression in vitro and in a mouse model of Metabolic Dysfunction-Associated Steatohepatitis (MASH). These findings highlight mtRNA's role in SASP regulation and its potential as a therapeutic target for mitigating age-related inflammation.

DOI: https://doi.org/10.1038/s41467-025-66159-z
bioRxiv. 2025 Dec 01. pii: 2025.11.28.691259. [Epub ahead of print]

Hyperactive Rac converts sublethal nibbling to lethal phagocytosis in vivo.

Abhinava K Mishra, Lauren Penfield, Morgan Smith, Denise Montell.

The small GTPase Rac is an essential regulator of cell shape, migration, macropinocytosis and phagocytosis. We recently reported that expression of constitutively active Rac G12V is sufficient to cause a few migratory cells called border cells to cannibalize nurse cells in the Drosophila ovary. Building on that insight, we engineered mammalian Rac-enhanced chimeric-antigen-receptor macrophages (RaceCAR-Ms) to avidly engulf and kill cancer cells. Here we investigate the cellular and molecular mechanisms by which border cells efficiently kill the much larger nurse cells. Surprisingly, wild type border cells normally nibble on nurse cells as they migrate between them, and Rac G12V causes border cells to take larger, lethal bites. These larger bites trigger rapid germline shrinkage, nuclear damage, and caspase activation, which spreads through the nurse cell syncytium. Then, many somatic follicle cells join in to engulf the dying germline. Rac and the engulfment receptor Draper are critical for both sublethal nibbling and lethal phagocytosis. Using clonal analysis, we show small groups of follicle cells expressing Rac G12V induced caspase activation in neighboring follicle cells while larger Rac G12V clones were required to cause germline killing. Increasing Draper expression or JNK activity in border cells also caused germline death, in a Rac-independent manner, suggesting that border cells can be activated to kill through multiple mechanisms. The series of events elucidated here reveals how hyperactivated Rac expressed in a few cells can trigger destruction of a much larger mass of cells.
Significance Statement: Rac is a key protein in the cellular eating process called phagocytosis. Rac hyperactivity enhances the consumption of tumor cells by chimeric antigen receptor-macrophages (CAR-M), a promising type of cellular immunotherapy. Elucidating the mechanisms by which hyperactive Rac enhances cell killing may lead to improvements in CAR-M. Key insights into the in vivo effects of Rac have come from studying Drosophila oogenesis. Here we report molecular and cellular mechanisms by which hyperactivated Rac stimulates migratory cells to engulf and kill much larger cells in the fly ovary, ultimately resulting in destruction of the entire tissue. These insights have implications for how hyperactivating Rac might improve antibody and CAR-M therapies for cancer and other diseases.

DOI: https://doi.org/10.1101/2025.11.28.691259
Cell Death Dis. 2025 Dec 14.

Ferroptosis inhibition protects against α-synuclein-related neuronal cell death.

Naďa Majerníková, Maria J Caiado, Renée I Seinstra, Suzanne Couzijn, María E Goya, Casandra Salinas Salinas, Hannah Truong, Tineke van der Sluis, Anneke Miedema, Leon C L T van Kempen, Gawain McColl, Ellen A A Nollen, Amalia M Dolga, Wilfred F A den Dunnen.

Parkinson's disease (PD), characterized by α-synuclein (α-syn) pathology, affects millions of people worldwide. While current treatments mainly symptomatically address the motor aspects of PD, they lack efficacy in delaying or halting the degenerative process. Ferroptosis, a type of programmed cell death characterized by iron-dependent lipid peroxidation, has been previously linked to PD. Advancing the development of neuroprotective treatments hinges on comprehending the interplay between PD's pathological hallmarks and cell death. We examined six ferroptosis-related markers (ferroportin, ferritin, NCOA4, cytochrome c, GPX4, and 4HNE) in mesencephalic tissues from 10 PD patients and 11 age-matched controls. In post-mortem brains of controls, several ferroptosis-related markers were differentially expressed in functional subregions of the substantia nigra (SN), suggesting differential ferroptosis vulnerability. Moreover, ferritin and ferroportin levels were reduced in relation to α-synuclein pathology, indicating impaired iron storage and export, and suggesting increased vulnerability to ferroptosis in Parkinson's disease. Additionally, using digital spatial transcriptomics, we revealed ferroptosis-related differentially expressed genes (DEGs) in PD, which altogether pointed towards higher ferroptosis vulnerability in PD compared to control brains. To support our post-mortem findings, we used in vitro models (LUHMES neurons and mouse cortical neurons (PCNs)) and an α-syn overexpression C. elegans model. Co-treatment with low concentrations of α-syn and RSL3, which alone did not cause cell death, increased neuronal vulnerability to cell death, which was mitigated by ferrostatin-1 (Fer-1) but not deferoxamine (DFO) in cortical and dopaminergic neurons. Finally, α-syn expression in C. elegans increased iron levels, exacerbated by ferritin knockdown and reduced by DFO, which decreased α-syn inclusions. These results indicate that α-syn-related cell death can be altered by ferroptosis inhibition, and targeting the ferroptosis pathway could reduce or slow cell death associated with PD pathology. However, ferroptosis vulnerability appears cell- and model-dependent, suggesting effective therapeutic strategies may require a more comprehensive approach, targeting multiple aspects of the pathway while considering timing to achieve optimal outcomes.

DOI: https://doi.org/10.1038/s41419-025-08319-z