bims-mihora 2026-02-22 papers

bims-mihora

Biomed News

on Mitohormesis, repair and aging

Issue of 2026–02–22
thirteen papers selected by
Lisa Patel, Istesso

Integrated Stress Response Promotes Acute Liver Failure by Activating SETD7 and Enhancing NLRP3 Methylation.
De novo design of protein binders that target DELE1 to inhibit the mitochondrial stress response.
Characterizing mitochondrial phenotypes and MERCS in aged human skeletal muscle myoblasts.
Intestinal stem cell damage caused by specific amino acid deprivation is linked to a potent integrated stress response triggered by the direct sensing of stem cells.
Mitochondrial TRPV1 exacerbates cognitive deficits in sepsis-associated encephalopathy by driving microglial metabolic reprogramming.
Role of CR6-Interacting Factor 1 (Crif1) in Cardiac Mitochondrial Structure and Stress-Induced Functional Decline.
The autophagy-senescence axis as a threshold model of aging and therapeutic targeting.
Dynamin-Related Protein 1-Dependent Disruption of Mitochondrial Homeostasis Drives Blue Light-Induced Epithelial-Mesenchymal Transition in Retinal Aging.
Mitochondria: the central hub linking exercise to enhanced cardiac function.
The Intracellular C5a-mtC5aR1 Axis Promotes Necroptosis in Dry Eye Through DRP1-Mediated Mitochondrial Dysfunction.
Variants in MTNAP1 underlie a neurodegenerative disorder by impairing mitochondrial stability.
CREG1 Attenuates Osteoarthritis Progression by Suppressing Chondrocyte Pyroptosis Through the PINK1/Parkin-Mediated Mitophagy Pathway.
The integrated stress response promotes immune evasion through lipocalin 2.

Mol Ther. 2026 Feb 16. pii: S1525-0016(26)00102-4. [Epub ahead of print]

Integrated Stress Response Promotes Acute Liver Failure by Activating SETD7 and Enhancing NLRP3 Methylation.

Zhentian Nie, Xiaohan Liu, Hongli Zhang, Zhengyang Chen, Xiaoyan Sun, Yuting Li, Yawei Kong, Hongyan Shu, Wei Chen.

While suppression of the integrated stress response (ISR) has been shown to restore proteostasis and mitigate organ injury in various diseases, its role in acute liver failure (ALF) remains poorly defined. Herein we discovered that during drug-induced ALF, hepatocytes exhibited early and transient activation of the eIF2α-ATF4 signaling pathway, whereas macrophages displayed delayed but sustained activation. Hepatocyte-specific deletion of ATF4 (ATF4ΔHep) significantly protected mice from acetaminophen (APAP)-induced liver injury, whereas myeloid-specific ATF4 deletion (ATF4ΔMye) increased susceptibility. Protection in ATF4ΔHep mice was associated with reduced hepatic necrosis, apoptosis, neutrophil infiltration, proinflammatory cytokine production, and serum ALT/AST levels. Pharmacological inhibition of ISR using ISRIB similarly ameliorated ALF, underscoring its therapeutic potential and the stage-dependent dual role of ISR signaling. Mechanistically, ATF4 in hepatocytes promoted mitochondrial dysfunction and inflammatory responses via the SETD7-NLRP3/IL-1β axis. ATF4 transcriptionally upregulated SETD7, a non-histone methyltransferase that methylates NLRP3 at lysine residues K192 and K684 within the NACHT and LRR domains, thereby stabilizing NLRP3 and enhancing inflammasome activation. The biphasic role of ATF4 was further validated in a CCl4-induced acute liver injury model. These findings identify the ATF4-SETD7-NLRP3 axis as a key regulator of hepatic inflammasome homeostasis and suggest it as a promising therapeutic target for ALF treatment.

DOI: https://doi.org/10.1016/j.ymthe.2026.02.016
bioRxiv. 2026 Feb 12. pii: 2025.12.22.695711. [Epub ahead of print]

De novo design of protein binders that target DELE1 to inhibit the mitochondrial stress response.

Rui Yang, Kaiyuan Zheng, McGuire Metts, Yiluo Wang, Danyan Yin, Kevin P Li, Agnieszka A Prazmowska, David F Kashatus, Brian Kuhlman, Jie Yang.

Mitochondrial stress activates the integrated stress response (ISR) through the mitochondrial protein DELE1, which relays stress signals to the cytosolic kinase HRI to induce ATF4. Dysregulation of DELE1-mediated signaling has been implicated in pathological conditions, yet molecular strategies to modulate DELE1 remain unavailable. Here, we report de novo designed proteins that bind DELE1, block its oligomerization, and inhibit DELE1-mediated ISR activation. Several designs form stable complexes with DELE1 and disrupt its oligomerization in vitro while preserving DELE1's ability to bind HRI. In cells, these designs suppress ATF4 induction during mitochondrial stress and impair the recovery of elongated mitochondrial morphology following transient insult. Crystal structure analysis, structural modeling, and targeted mutagenesis confirm that the designed proteins engage a critical interface required for DELE1 oligomerization. These findings establish DELE1 as a druggable target and demonstrate that de novo designed proteins offer precise tools to modulate this pathway, laying groundwork for therapeutic development.

DOI: https://doi.org/10.64898/2025.12.22.695711
PLoS One. 2026 ;21(2): e0343604

Characterizing mitochondrial phenotypes and MERCS in aged human skeletal muscle myoblasts.

Yufu Unten, Kazuaki Takafuji, Yumiko Masukagami, Isshin Shiiba, Keigo Horiuchi, Filip Husnik, Shigeru Yanagi, Norifumi Tateishi, Toshihide Suzuki.

Age-associated declines in skeletal muscle function are linked to cellular senescence and mitochondrial alterations, yet mitochondrial phenotypes in aged human myoblasts remain insufficiently characterized. Here, we examined primary skeletal muscle myoblasts from young and elderly donors to assess mitochondrial function, morphology, and mitochondria-endoplasmic reticulum (ER) contact sites (MERCS). Myoblasts from older donors exhibited senescence features, including elevated SA-β-gal activity and reduced Lamin B1 expression, accompanied by increased mitochondrial oxidative stress. Despite marked mitochondrial hyperfusion and increased mitochondrial DNA content, mitochondrial oxygen consumption rate and membrane potential per mitochondrial area were comparable between young and old cells. MERCS were significantly elevated in aged myoblasts and were reduced by scavenging mitochondrial reactive oxygen species (mtROS), indicating an association between oxidative stress and MERCS formation. These findings suggest that mitochondrial hyperfusion and enhanced MERCS accompany cellular aging in human myoblasts and may contribute to maintaining mitochondrial function under elevated oxidative stress.

DOI: https://doi.org/10.1371/journal.pone.0343604
Biochem Biophys Res Commun. 2026 Feb 11. pii: S0006-291X(26)00218-4. [Epub ahead of print]807 153454

Intestinal stem cell damage caused by specific amino acid deprivation is linked to a potent integrated stress response triggered by the direct sensing of stem cells.

Ayumi Kozai, Takumi Satoh, Yoshiko Sugita-Konishi, Makoto Shimizu, Ken Iwatsuki, Miki Tadaishi, Kazuo Kobayashi-Hattori.

  Amino acid deprivation, particularly deficiencies in methionine (Met) or glutamine (Gln), disrupts intestinal stem cells (ISCs), causes growth suppression, and induces cell death. We previously found that among the branched-chain amino acid (BCAA), leucine and isoleucine deprivation maintain ISC survival, whereas valine (Val) deprivation induces ISC impairment, which is characterized by suppressed proliferation and increased cell death; however, the mechanisms underlying these divergent cell fates remain largely unclear. We here focused on the integrated stress response (ISR) as a regulator of cell fate under amino acid deprivation using mouse intestinal organoids and ISCs isolated from organoids. Deprivation of each BCAA uniformly suppressed global translation, whereas only Val deprivation induced activation through phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α) and a persistent increase in the mRNA expressions of activating transcription factor 4, C/EBP homologous protein, and growth arrest and DNA damage-inducible 34, indicating a potent and sustained ISR. Analysis using ISCs isolated by cell sorting revealed that only Val deprivation markedly increased p-eIF2α levels and reduced organoid formation. Furthermore, Met and Gln deprivation resulted in similar responses to Val deprivation in organoids and isolated ISCs. Taken together, these results suggest that Val, Met, and Gln deprivation induce a potent ISR through direct sensing by ISCs, with the response associated with stem cell damage.

Keywords:  Amino acids; Glutamine; Integrated stress response; Intestinal stem cells; Methionine; Organoids; Valine

DOI:  https://doi.org/10.1016/j.bbrc.2026.153454
Free Radic Biol Med. 2026 Feb 13. pii: S0891-5849(26)00130-9. [Epub ahead of print]247 448-468

Mitochondrial TRPV1 exacerbates cognitive deficits in sepsis-associated encephalopathy by driving microglial metabolic reprogramming.

Zhongmin Fan, Lixia Du, Lu Yin, Hao Liu, Mengyun Li, Jing Li, Fuhong Liu, Lin Yang, Jin Li, Qi Wang, You Wu, Hongwei Ma, Xijing Zhang.

Transient receptor potential vanilloid 1 (TRPV1), a canonical non-selective cation channel predominantly expressed on the cellular membrane of peripheral sensory neurons, is responsible for perceiving physical and chemical stimuli. Accumulating evidence indicates TRPV1 expression in the central nervous system, the role of which remains elusive. Here, we demonstrate that, distinct from neurons or astrocytes, TRPV1 is distributed on the mitochondrial membrane of microglia in the hippocampus, mediating neurotoxic microglial responses during both acute and convalescent stages of sepsis by disrupting mitochondrial dynamics. During the pathogenesis of sepsis-associated encephalopathy (SAE), hippocampal microglia exhibit elevated TRPV1 expression concurrent with a pro-inflammatory state. Genetic ablation of TRPV1 or application of TRPV1 antagonist attenuates microglial inflammatory polarization and phagocytic dysfunction both in vivo and in vitro. This mitigates immoderate neuroinflammation and aberrant synaptic pruning, thereby reshaping synaptic plasticity and ameliorating cognitive deficits in SAE. Mechanistically, TRPV1 reprograms microglial phenotype with dysregulated capability for glycometabolism by affecting their mitochondrial function. Following LPS challenge, TRPV1 activation exacerbates mitochondrial damage and impairs ATP production in microglia, resulting in bioenergetic failure and excessive generation of mitochondrial reactive oxygen species (mtROS) and mtDNA. Conversely, TRPV1 depletion enhances oxidative phosphorylation capacity of microglia to counteract LPS toxicity. TRPV1 silencing further promotes the formation of cristae-deficient mitochondria, sustaining reductive proline biosynthesis and shifting microglia toward a protective pattern. Collectively, our findings suggest that TRPV1 compromises the metabolic reprogramming of microglia by perturbing mitochondrial dynamics, revealing a novel therapeutic target for SAE intervention.

DOI: https://doi.org/10.1016/j.freeradbiomed.2026.02.033
Korean Circ J. 2025 Dec 16.

Role of CR6-Interacting Factor 1 (Crif1) in Cardiac Mitochondrial Structure and Stress-Induced Functional Decline.

Seon-Ah Jin, Hee Jung Seo, Byung-Kwan Lim, Jin-Ok Jeong.

   BACKGROUND AND OBJECTIVES: CR6-interacting factor 1 (CRIF1) is essential for the synthesis and insertion of mitochondrial oxidative phosphorylation (OXPHOS) complexes. Although Crif1 deficiency has been linked to mitochondrial dysfunction in various tissues, its role in cardiac function remains unclear. Therefore, this study aimed to investigate the role of Crif1 in regulating mitochondrial function in the heart.
METHODS: To determine the role of Crif1 and examine mitochondrial dysfunction in the heart, we generated cardiac-specific Crif1 knock-down mice using a Myh6-Cre system. Mitochondrial function was assessed by measuring oxygen consumption rates. Histological and echocardiographic examinations were performed at baseline and 2 weeks after isoproterenol infusion.
RESULTS: Crif1 knock-down in the heart led to structural mitochondrial abnormalities and decreased maximal oxygen consumption rates in cardiomyocytes. Although cardiac-specific Crif1 knock-down resulted in mitochondrial dysfunction, the cardiac phenotype remained normal showing preserved ejection fraction (EF) and fractional shortening (FS). However, cardiac dysfunction was aggravated under isoproterenol-induced stress, resulting in a decreased EF and FS. Cardiac hypertrophy, a typical adaptive response to isoproterenol stimulation, was attenuated.
CONCLUSIONS: These findings suggest that Crif1 is critical for maintaining the structure and function of mitochondria in cardiomyocytes. Additionally, mitochondrial abnormalities in the heart impair stress adaptation, leading to aggravated cardiac dysfunction under stress.

Keywords:  Cardiomyopathies; Crif1 protein, mouse; Heart failure; Mitochondria; Oxidative phosphorylation

DOI:  https://doi.org/10.4070/kcj.2025.0155
Redox Biol. 2026 Feb 10. pii: S2213-2317(26)00077-7. [Epub ahead of print]91 104079

The autophagy-senescence axis as a threshold model of aging and therapeutic targeting.

Md Entaz Bahar, Jin Seok Hwang, Trang Huyen Lai, Kazi-Marjahan Akter, Rizi Firman Maulidi, Deok Ryong Kim.

  Autophagy and cellular senescence are fundamental stress-response programs that critically shape aging and disease progression, yet their functional relationship has remained paradoxical. Autophagy is traditionally viewed as a cytoprotective process that preserves cellular homeostasis and delays senescence. In contrast, emerging evidence demonstrates that autophagy is also indispensable for the survival and pathological activity of established senescent cells. In this review, we propose a "threshold model" to reconcile these opposing roles and to provide a unified framework linking signal transduction, organelle quality control, and therapeutic intervention. According to this model, autophagy exerts stage-dependent functions governed by stress intensity and disease progression. Below a critical damage threshold, robust autophagic flux suppresses senescence initiation by maintaining mitochondrial integrity, limiting oxidative stress, and preserving proteostasis. Once this threshold is exceeded, autophagy is functionally reprogrammed to sustain the metabolic and biosynthetic demands of senescent cells, including production of the senescence-associated secretory phenotype (SASP). We highlight key signaling nodes that regulate this transition, including mTORC1, AMPK, p53, and p62, as well as spatial and organelle-specific mechanisms such as the TOR-autophagy spatial coupling compartment (TASCC), mitophagy failure, lipophagy blockade, and aberrant nucleophagy. These processes converge on innate immune pathways, notably cGAS-STING and NF-κB signaling, to drive chronic inflammation and tissue dysfunction. Importantly, we extend this mechanistic framework to clinical translation, synthesizing evidence from ongoing trials in cancer, neurodegeneration, metabolic liver disease, and fibrosis. We argue that effective targeting of the autophagy-senescence axis requires precision gerontology, integrating dynamic biomarkers to guide stage-specific interventions-autophagy activation for prevention and autophagy inhibition or senolysis for established disease. This threshold-based perspective provides a rational foundation for next-generation therapeutic strategies targeting aging and age-related disorders.

Keywords:  Autophagy; Cellular stress; Senescence; Targeted senotherapy; Threshold-model

DOI:  https://doi.org/10.1016/j.redox.2026.104079
Aging Cell. 2026 Feb;25(2): e70416

Dynamin-Related Protein 1-Dependent Disruption of Mitochondrial Homeostasis Drives Blue Light-Induced Epithelial-Mesenchymal Transition in Retinal Aging.

Zhi-Yuan Li, Dashuang Yang, Yongxia Huang, Yintian Li, Tianyun Zhao, Ying Xu.

  Age-related macular degeneration (AMD) stands as a leading cause of blindness in the elderly, yet the fundamental aging processes that underpin its pathogenesis remain incompletely defined. The dysfunction of retinal pigment epithelial (RPE) cells is a central event in AMD, a process that shares key hallmarks with broader cellular aging, particularly the progressive decline in mitochondrial function. In this study, we investigated how a common environmental stressor-blue light-triggers a key pathological transformation, epithelial-mesenchymal transition (EMT), in RPE cells by specifically disrupting mitochondrial dynamics, a core pillar of cellular aging. Using an in vitro model of human RPE cells, we demonstrated that blue light exposure induces a marked shift in mitochondrial dynamics towards excessive fission. This imbalance directly resulted in mitochondrial dysfunction, elevated oxidative stress, and served as the critical driver for the initiation of EMT. Importantly, pharmacological inhibition of the mitochondrial fission GTPase Dynamin-related protein 1 (Drp1) with Mdivi-1 effectively restored mitochondrial network homeostasis, rescued mitochondrial function, and fully reversed the EMT phenotype. These findings were corroborated in a mouse model of blue light-induced retinal damage, where Drp1 inhibition successfully preserved retinal light responses, mitigated structural degeneration, and slowed disease progression. Our study demonstrates that Drp1-mediated excessive mitochondrial fission drives EMT in RPE cells under blue light, linking this mechanism to AMD progression. Consequently, targeting mitochondrial dynamics to maintain cellular homeostasis emerges as a promising and broadly applicable geroscience-based strategy for mitigating age-related tissue dysfunction.

Keywords:  Drp1; age‐related macular degeneration; epithelial‐mesenchymal transition; mitochondrial dynamics; oxidative stress; retinal pigment epithelial

DOI:  https://doi.org/10.1111/acel.70416
Front Physiol. 2026 ;17 1747133

Mitochondria: the central hub linking exercise to enhanced cardiac function.

Jiaqin Cai, Tutu Wang, Shunchang Li.

  Sedentary lifestyle is a major risk factor for the occurrence and development of cardiovascular disease, which remains one of the leading contributors to global morbidity and mortality. Beyond inducing endothelial dysfunction, prolonged sedentary patterns trigger chronic inflammation and disrupt endogenous antioxidant defenses, resulting in mitochondrial dysfunction in cardiomyocytes and subsequent impairment of cardiac health. In contrast, regular physical exercise serves as an effective lifestyle intervention that mitigates sedentary-related cardiac damage and improves cardiac function. Mitochondria, as central organelles governing cellular survival and death, are thought to play a pivotal role in mediating the cardioprotective effects of exercise. However, the precise mitochondrial mechanisms underlying these benefits remain incompletely defined. This review aims to summarize current evidence on how exercise regulates mitochondrial function in the heart, with particular emphasis on recent advances linking mitochondrial respiration, dynamics, calcium homeostasis, inflammatory signaling, and oxidative stress to cardiac health. We further propose that exercise-induced improvements in mitochondrial function constitute a core mechanism underlying its cardioprotective effects. By comparing mitochondrial alterations under sedentary and exercise conditions, we provide a clearer mechanistic perspective on how lifestyle behaviors shape cardiac health. Furthermore, this paper also discusses signaling pathways that position mitochondria as key targets of exercise-induced cardiac protection.

Keywords:  exercise; heart; inflammatory response; mitochondria; oxidative stress

DOI:  https://doi.org/10.3389/fphys.2026.1747133
Invest Ophthalmol Vis Sci. 2026 Feb 02. 67(2): 35

The Intracellular C5a-mtC5aR1 Axis Promotes Necroptosis in Dry Eye Through DRP1-Mediated Mitochondrial Dysfunction.

Limei Wang, Haijing Yan, Yetao Shen, Songlin Xin, Chenyu Dong, Jiuxiao Li, Yueping Ren, Wei Chen, Qinxiang Zheng.

Purpose: As a multifactorial ocular surface pathology, dry eye (DE) is marked by inflammation and epithelial damage. While mitochondrial dysfunction and oxidative stress are implicated, the mechanisms driving cornea epithelial cell damage remain unclear. This study investigates the role of C5a-mitochondrial C5a receptor 1 (mtC5aR1) in human corneal epithelial cells (HCECs) during DE pathogenesis.
Methods: We examined C5aR1 expression and localization in HCECs under normal and hyperosmotic stress (mimicking DE) using molecular techniques. The functional role of the intracellular C5a-mtC5aR1 axis was assessed through pharmacological inhibition (JPE-1375 and PMX-53) and analysis of downstream signaling (RIPK3/MLKL-mediated necroptosis, DRP1 activation, mitochondrial function, and inflammatory cytokine production). The therapeutic potential of JPE-1375 was further evaluated in a DE mouse model, assessing corneal epithelial damage and inflammation.
Results: We demonstrate, for the first time, that HCECs express C5aR1 on the outer mitochondrial membrane (mtC5aR1), and its expression is upregulated in DE conditions. Hyperosmotic stress-induced local C5a production in HCECs activates mtC5aR1, triggering DRP1-mediated mitochondrial dysfunction and initiating RIPK3/MLKL-dependent necroptosis. Pharmacological blockade of mtC5aR1 with JPE-1375 significantly attenuated necroptosis, restored mitochondrial function, and reduced inflammatory cytokine production in stressed HCECs. Furthermore, JPE-1375 treatment mitigated corneal epithelial damage and inflammation in the DE mouse model.
Conclusions: Our findings identify the intracellular C5a-mtC5aR1-DRP1 axis as a novel regulatory mechanism driving necroptosis in DE. Targeting this pathway represents a potential therapeutic approach to reduce inflammation and corneal damage in DE.

DOI: https://doi.org/10.1167/iovs.67.2.35
NPJ Genom Med. 2026 Feb 20.

Variants in MTNAP1 underlie a neurodegenerative disorder by impairing mitochondrial stability.

Abhishek Kumar, Smita Saha, Nazim Nasir, Vishal Gaurav, Yogendra Pratap Mathuria, Shailesh Kumar Gupta, Akash Ranjan, Debasish Kumar Ghosh.

Mutations in genes encoding mitochondrial proteins are increasingly recognized as a major cause of neurodegenerative disorders, owing to the role of mitochondria in neuronal energy metabolism and signaling. Here, we investigate MTNAP1 (mitochondrial nucleoid-associated protein 1) as a novel gene associated with an autosomal recessive neurodevelopmental disorder characterized by progressive cerebral and cerebellar atrophy. Three affected probands from two unrelated families presented with global developmental delay, ataxia, spasticity, seizures, and progressive neurological decline, with MRI revealing generalized cerebral and cerebellar volume loss and thinning of the corpus callosum. Trio-based exome sequencing uncovered two ultra-rare, biallelic loss-of-function variants in MTNAP1: a homozygous missense variant (p.G553R) in two siblings and a homozygous nonsense variant (p.Y13X) in an unrelated proband. Functional studies in proband-derived fibroblasts and MTNAP1-silenced neuronal cells implicated profound mitochondrial fragmentation, reduced oxidative phosphorylation capacity, increased reactive oxygen species accumulation, and premature senescence-like stress responses. Structural modeling and biophysical analyses revealed that the p.G553R variant destabilizes the MTNAP1 fold, disrupts its DNA- and membrane-binding interfaces, and induces aberrant aggregation, leading to loss of mitochondrial integrity. Collectively, our findings suggest MTNAP1 as a crucial regulator of mitochondrial homeostasis and identify pathogenic MTNAP1 variants as the cause of a novel, progressive neurodegenerative disorder.

DOI: https://doi.org/10.1038/s41525-026-00554-3
Biotechnol J. 2026 Feb;21(2): e70196

CREG1 Attenuates Osteoarthritis Progression by Suppressing Chondrocyte Pyroptosis Through the PINK1/Parkin-Mediated Mitophagy Pathway.

Xianming Fei, Shuanggong Liu, Guangxu Song, Shuhang Dong, Ziyi Song, Wei Xu.

   BACKGROUND: Osteoarthritis (OA) is a progressive degenerative disorder driven by complex pathogenic mechanisms. Increasing evidence indicates that NLRP3 inflammasome-mediated chondrocyte pyroptosis contributes critically to OA progression. Cellular repressor of E1A-stimulated gene 1 (CREG1), a secreted glycoprotein involved in cellular homeostasis and lysosomal function, has not been well characterized in OA. This study aimed to investigate the role of CREG1 in OA and its underlying molecular mechanisms.
METHODS: Human knee OA cartilage samples were analyzed to evaluate the association between CREG1 expression and chondrocyte pyroptosis. An LPS/ATP-induced in vitro pyroptosis model was used to assess the effects of CREG1 on chondrocyte apoptosis, extracellular matrix (ECM) degradation, NLRP3 inflammasome activation, and PINK1/Parkin-dependent mitophagy. Cyclosporin A (CsA) was applied to inhibit mitophagy.
RESULTS: CREG1 expression was significantly reduced in OA cartilage and negatively correlated with chondrocyte pyroptosis. CREG1 silencing aggravated apoptosis and ECM degradation, promoted NLRP3 inflammasome activation, impaired mitophagy, and disrupted mitochondrial function. Conversely, CREG1 overexpression restored PINK1/Parkin-mediated mitophagy, improved mitochondrial homeostasis, and suppressed NLRP3 inflammasome activation. These effects were abolished by CsA treatment.
CONCLUSIONS: CREG1 protects against OA progression by suppressing NLRP3 inflammasome-driven chondrocyte pyroptosis through activation of PINK1/Parkin-dependent mitophagy, highlighting CREG1 as a potential therapeutic target.

Keywords:  CREG1; NLRP3 inflammasome; mitophagy; osteoarthritis; pyroptosis

DOI:  https://doi.org/10.1002/biot.70196
Nature. 2026 Feb 18.

The integrated stress response promotes immune evasion through lipocalin 2.

Jozef P Bossowski, Ray Pillai, John Kilian, Angela Wong Lau, Mari Nakamura, Ali Rashidfarrokhi, Yuan Hao, Ruxuan Li, Katherine Wu, Takamitsu Hattori, Eliezra Glasser, Akiko Koide, Lidong Wang, Andre L Moreira, Cristina Hajdu, Sahith Rajalingam, Sarah E LeBoeuf, Hortense Le, Seungeun Lee, Jin Woo Oh, Cheolyong Joe, Hyemin Kim, Chan-Young Ock, Se-Hoon Lee, Hao Wang, Angana A H Patel, Volkan I Sayin, Aristotelis Tsirigos, Kwok-Kin Wong, Sergei B Koralov, Mario Pende, Francisco J Sánchez-Rivera, Diane M Simeone, Ioannis K Zervantonakis, Shohei Koide, Thales Papagiannakopoulos.

Cancer cells activate the integrated stress response (ISR) to adapt to stress and resist therapy1. ISR signals converge on activating transcription factor 4 (ATF4), which controls cell-intrinsic transcriptional programs that are involved in metabolic adaptation, survival and growth2,3. However, whether the ISR-ATF4 axis influences anti-tumour immune responses remains mostly unknown. Here we show that loss of ATF4 decreases tumour progression considerably in immunocompetent mice, but not in immunocompromised ones, by enhancing T cell-dependent anti-cancer immune responses. An unbiased genetic screen of ATF4-regulated genes identifies lipocalin 2 (LCN2) as the principal ATF4-dependent effector that impairs anti-tumour immunity by favouring infiltration with immunosuppressive interstitial macrophages. Furthermore, we find that LCN2 promotes T cell exclusion and immune evasion in preclinical mouse models, and correlates with decreased T cell infiltration in patients with lung and pancreatic adenocarcinomas. Anti-LCN2 antibodies promote robust anti-tumour T cell responses in mouse models of aggressive solid tumours. Our study shows that the ATF4-LCN2 axis has a cell-extrinsic role in suppressing anti-cancer immunity, and could pave the way for an immunotherapy approach that targets LCN2.

DOI: https://doi.org/10.1038/s41586-026-10143-0