An ER stress-responsive RNA rheostat for programmable gene and mRNA therapies

Proteostasis pathways offer opportunities for engineering cellular control systems. Ogurlu et al. repurpose IRE1α-dependent XBP1 splicing to create RNA rheostats that link ER stress sensing with transgene expression, establishing a feedback mechanism that limits protein overexpression and improves control of gene and mRNA therapies.

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Metabolic danger signals: TCA cycle metabolites regulate immunity and disease

Ryan and Zanoni redefine TCA cycle metabolites as metabolic danger signals that shape immunity across infections, inflammation, and cancers. They introduce the concept of metabolic DAMPs (“metaDAMPs”) as a unifying framework for understanding immune activities of endogenous metabolites and outline emerging technologies positioning immunometabolism as a tractable axis for therapeutic intervention.

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The BAX/BAK apoptotic checkpoint polices entry to therapy-induced senescence

Cell fate decisions after genotoxic stress are critical determinants of therapeutic outcome. Gallagher Aldave et al. identify the BAX/BAK apoptotic checkpoint as a key regulator of entry to therapy-induced senescence and show that senescent cells acquire vulnerabilities to Bcl-xL and Mcl-1 targeting that can be leveraged to promote apoptosis.

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Resolving the subcellular redox landscape of Coenzyme Q

Accurate analysis of Coenzyme Q (CoQ) redox status is limited by oxidation during sample preparation. Kim et al. develop a dual-isotope-based correction platform that restores native CoQ redox states across biological matrices and enables subcellular redox profiling. This approach provides a valuable tool for studying ferroptosis, mitochondrial metabolism, and redox biology.

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Repurposing simeprevir uncovers a druggable KPNB1-p65-BCL2 survival axis in cancer

Drug repurposing can uncover unexpected therapeutic opportunities in cancer. Li et al. identify the antiviral drug simeprevir as an inhibitor of KPNB1-mediated NF-κB signaling, uncovering a KPNB1-p65-BCL2 survival axis and establishing simeprevir as a promising therapeutic lead.

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TRPM8 is a non-canonical target of 7-nitrobenzodiazepines

Benzodiazepines are a major class of drugs that work by activating GABAA receptors. Elkin et al. show that clonazepam, a 7-nitrobenzodiazepine, also robustly activates TRPM8 ion channels. The engagement of TRPM8 via clonazepam may underlie clonazepam’s efficacy in treating a painful condition known as burning mouth disorder.

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A protective human antibody reveals a quaternary epitope on the Epstein-Barr virus fusion apparatus

Protective epitopes on the EBV fusion apparatus remain incompletely defined. Zhao et al. identify 4G12, a human antibody targeting a quaternary epitope on the gHgL-gp42 complex that neutralizes infection and protects humanized mice, revealing a vulnerable site for vaccine design.

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Multinuclear iron enzymes expand RiPP chemical diversity to enable bacterial oxidative stress defense

Feng et al. show that multinuclear iron enzymes install 5-thiooxazole modifications on RiPPs, enhancing bacterial survival under oxidative stress. This work reveals the biosynthetic logic and functional impact of a widespread chemical transformation, linking RiPP diversification to stress adaptation rather than traditional roles in metal homeostasis.

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N-acetyltransferase 10 regulates chemokine expression in keratinocytes and promotes atopic dermatitis

Shao et al. identified NAT10-mediated RNA acetylation as a key epitranscriptomic regulator of atopic dermatitis. NAT10 stabilized RELB mRNA to coordinate a pro-inflammatory checkpoint in keratinocytes that drove neutrophil recruitment. Targeting NAT10/ac4C axis with Remodelin offers a potent chemical strategy for treating inflammatory skin diseases.

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Dual-function PROTAC suppresses ferroptosis and restores neuronal function via brain-targeted delivery

Ma et al. develop a dual-function PROTAC that degrades ACSL4 to reduce PUFA-containing membrane phospholipids while activating the PPARγ antioxidant pathway to enhance cellular antioxidant defense. Brain-targeted delivery of dACSL4 via biodegradable lipid nanoparticles effectively suppresses neuronal ferroptosis, reducing dopaminergic neuron loss and improving motor function in Parkinson’s disease models.

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Aptamer targeting HMGB1 attenuates inflammatory disease via domain-specific antagonism

Zhang et al. describe ZH-1a, a high-affinity DNA aptamer that preferentially targets the HMGB1 B-box domain. By neutralizing extracellular HMGB1, ZH-1a suppresses inflammatory signaling, protects against acute inflammatory injury and polymicrobial sepsis, and enhances methotrexate efficacy in an arthritis model.

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CXCR4-EGFR heteromers show ligand-dependent changes in conformation and signaling

Comez et al. show that CXCR4 and EGFR form oligomeric signaling complexes detected by NanoBRET and nanobody-based PLA. These complexes alter Gi and β-arrestin coupling following the activation of both receptors and were also detected in native cancer cells, revealing how receptor co-expression may reshape signaling outputs in cancer.

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Pyroptosis across species and its potential impact on host defense against zoonotic pathogens

Why do some animals carry zoonotic pathogens, like SARS-CoV-2, with little immune response against them, yet in humans, they induce severe inflammatory disease? Ho and Bryant compare the variation in genes that regulate pyroptosis (lytic cell death) across animal species compared to humans as a potential contributory mechanism.

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Kinetic control of macrophage death by PTM-turnover crosstalk in infection and inflammation

Saha et al. propose a “turnover-first” hypothesis describing how macrophages decide between survival, pyroptosis, apoptosis, necroptosis, and PANoptosis during infection and inflammation. They present evidence that protein synthesis, post-translational modification codes, and selective degradation via the ubiquitin-proteasome system, autophagy, and ESCRT machinery create a kinetic timer setting death thresholds.

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PANoptosis in life and death across cell types: From innate immunity to therapeutic implications

Inflammatory cell death, PANoptosis, shapes immunity, tissue pathology, and the balance between health and disease. Zengeler et al. critically evaluate emerging evidence that PANoptosis operates across immune, non-immune, and cancer cells, providing a framework for understanding its molecular regulation, physiological and pathological functions, and therapeutic potential.

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Metabolic underpinnings of cuproptosis

Jiang et al. review the metabolic foundations of cuproptosis, a copper-driven form of regulated cell death linked to mitochondrial metabolism. They discuss how copper homeostasis, lipoylation, and redox pathways control cuproptosis and highlight emerging therapeutic opportunities to exploit this metabolic vulnerability in cancer and other diseases.

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Licensed to pore: Gasdermins in action

Ketelut-Carneiro, Mathur, and Fitzgerald review the mechanisms and regulation of the different gasdermins (GSDMs) in pyroptosis. They provide a comprehensive overview of the role of GSDMs across infectious and inflammatory diseases and cancer, highlighting key unanswered questions and challenges in targeting GSDMs for therapeutic strategies.

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The pyruvate dehydrogenase complex at the crossroads of cancer metabolism and cell death

Cai. et al. highlight the PDK-PDHC axis as a central metabolic node connecting tumor metabolism with regulated cell death. They explore PDHC structural plasticity and regulatory mechanisms, emphasizing the translational implications of targeting PDH-related metabolic vulnerabilities for context-specific precision cancer therapy.

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Too much of a good thing: Promotion of tumor progression and metastasis by apoptotic cells

Most tumor therapies induce the apoptotic pathway in tumor and bystander cells, but apoptotic cells may paradoxically enhance tumor growth and metastasis. Hagan et al. consider the tumor-promoting effects of apoptotic cells and discuss approaches to overcome these effects.

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Redundant or resilient? A systems view of ferroptosis surveillance mechanisms

Liang et al. outline how cells deploy coordinated surveillance mechanisms, including the GPX4 axis, radical trapping antioxidants, and lipid remodeling pathways, to prevent ferroptosis across cellular organelles and tissues. This review provides a coherent framework for understanding ferroptotic vulnerability in health and disease and highlights opportunities for therapeutic intervention.

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Mechanism and regulation of programmed cell death in aging-related diseases

Xie et al. review how apoptosis, necroptosis, and pyroptosis drive aging-related diseases. They detail the molecular mechanisms of these programmed cell death pathways and highlight how targeting key nodes such as RIPK1 and NLRP3 offers therapeutic opportunities to break the cycle of inflammation and tissue degeneration in aging.

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Transcending cell death – The diverse roles of necroptosis signal adaptors in pathogen infection

Viruses are widely believed to evade host cell necroptosis to maximize their survival within the host. Huang, Li, and Chan challenge this paradigm by proposing that the host senses viral interference of necroptosis to tune the host response against the invading pathogen.

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Beyond the veil of cell death

The realization that cells can engage regulated cell death pathways yet survive represents a paradigm shift in the field. In this perspective, Green et al. explore the mechanisms enabling such “near-death” states and their consequences, reframing cell death pathway engagement as a reversible process, which impacts cell fate and function.

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BACH1 meets its match: Heme licenses BACH1 destruction to tune ferroptosis

In a recent issue of Molecular Cell, Ahmed and colleagues show that heme enables CRL2-FEM1B to recognize and degrade BACH1, linking metabolite-assisted substrate recruitment to ferroptosis regulation. This mechanism connects heme sensing, ubiquitin-mediated proteolysis, and transcriptional control of ferroptosis-protective genes, revealing a potential vulnerability in lung cancer.

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Meet the authors: Stella Ho and Clare Bryant

In an interview with Samantha Nelson, a scientific editor of Cell Chemical Biology, the authors of the minireview entitled “Pyroptosis across species and its potential impact on host defense against zoonotic pathogens” share their perspectives on their field and life as scientists.

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Emerging challenges, mechanisms, and therapeutic opportunities in cell death

Regulated cell death pathways play fundamental roles in development, tissue homeostasis, immunity, and disease and have emerged as attractive targets for therapeutic intervention. In a cell death mechanisms special issue of Cell Chemical Biology, this Voices piece asks researchers from a range of backgrounds the following questions: what recent advances in cell death research excite you most, what key challenges remain to be overcome, and what are the next big questions the field should address?

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Cell death mechanisms and physiological functions

Cell death research has evolved beyond understanding the fate of damaged cells to reveal a diverse network of regulated pathways with complex mechanisms that shape physiology and disease. This special issue highlights emerging mechanisms, physiological functions, and intricate crosstalk across the expanding landscape of cell death programs.

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Understanding protein ISGylation, a multifaceted posttranslational modification

Protein ISGylation is a ubiquitin-like post-translational modification primarily induced by interferon signaling. Shirley et al. review the enzymatic machinery governing ISG15 conjugation and deconjugation, highlighting chemical tools for measuring and inhibiting their activity, emerging chemical biology approaches for mapping ISGylomes, and pathophysiological implications in multiple disease states.

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