bims-mistre Biomed News
on Mito stress
Issue of 2025–12–28
fourteen papers selected by
Ellen Siobhan Mitchell, MitoQ
  1. Beyond Bioenergetics: Emerging Roles of Mitochondrial Fatty Acid Oxidation in Stress Response and Aging.
  2. Mitochondrial Dysfunction in Alzheimer's disease: Focus on Dynamics and Electron Transport Chain.
  3. Oral short-chain fatty acid-producing bacteria may be associated with biological age and cognition among the oldest old.
  4. Mitochondria in Developing Brain: Contribution of Deviations to Higher Susceptibility to Neurodegeneration in Latter Periods of Life.
  5. Growth differentiation factor 15: from stress response to clinical utility in chronic liver diseases.
  6. High-Frequency rTMS can Improve Depressive Symptoms by Promoting Mitochondrial Fusion.
  7. Identifying sex-specific biomarkers for intrinsic capacity decline in the aging population.
  8. Menopause hormone therapy and risk of mild cognitive impairment or dementia: a systematic review and meta-analysis.
  9. Synergistic Roles of FAHD-1 and PYC-1 in Mitochondrial Function, Behavior, and Longevity in C. elegans.
  10. Reversal of proteomic aging with exercise-results from the UK biobank and a 12-week intervention study.
  11. Suppressing Mitochondrial ROS Production is Beneficial in Multiple Preclinical Models of Human Disease.
  12. An orally active estrogen receptor-related receptor agonist, SLU-PP-915, enhances aerobic exercise capacity.
  13. Curcumin reprograms metabolic pathways and MAPK signaling to exert antidepressant effects.
  14. Exercise-induced β-hydroxybutyrate contributes to cognitive improvement in aging mice.
  1. Cells. 2025 Dec 09. pii: 1956. [Epub ahead of print]14(24):
    Beyond Bioenergetics: Emerging Roles of Mitochondrial Fatty Acid Oxidation in Stress Response and Aging.
    Surim Bang, So-Hyun Choi, Seung Min Jeong.
      Mitochondrial fatty acid oxidation (FAO) has long been recognized as a central pathway for energy production, providing acetyl-CoA, NADH, and FADH2 to sustain cellular growth and survival. However, recent advances have revealed that FAO exerts far broader roles beyond bioenergetics. FAO contributes to redox balance by generating NADPH for antioxidant defense, regulates protein acetylation through acetyl-CoA availability, and modulates stress signaling pathways to support cellular adaptation under nutrient or genotoxic stress. These emerging insights establish FAO as a metabolic hub that integrates energy homeostasis with redox regulation, epigenetic modification, and stress responses. Dysregulation of FAO has been increasingly implicated in aging and diverse pathologies, including cellular senescence, obesity, cancer and fibrosis. In this review, we highlight recent findings and provide an updated perspective on the expanding roles of mitochondrial FAO in stress responses and aging, with particular emphasis on its potential as a therapeutic target in age-associated diseases.
    Keywords:  acetylation; age-related diseases; fatty acid oxidation; redox homeostasis; stress response
    DOI:  https://doi.org/10.3390/cells14241956
  2. Aging Dis. 2025 Dec 21.
    Mitochondrial Dysfunction in Alzheimer's disease: Focus on Dynamics and Electron Transport Chain.
    Jiehui Li, Gajendra Kumar, Yuqing Yan, Mengmeng Wang, Ling Xu, Haige Wu, Ye Gao, Yi Wang, Yingyi Fan, Ying Bai.
      Alzheimer's disease (AD) is a progressive neurological disease characterized by a decline in cognitive abilities and memory loss. Mitochondrial dysfunction is a major factor in early pathological changes; however, its precise pathogenic mechanisms are not yet fully understood. Mitochondria are essential for neuronal energy generation, calcium ion balance regulation, apoptosis control, and production of reactive oxygen species. Among the various mitochondrial changes, the imbalance between fission and fusion is closely linked to β-amyloid deposition and tau pathology, forming a vicious cycle. The electron transport chain (ETC) produces more than 90% of cellular ATP and is damaged in AD. However, most studies simply refer to "mitochondrial dysfunction" in general terms without detailing specific changes in ETC complexes and their subunits. This review aims to provide a detailed overview of the dynamics and ETC complex dysfunction observed in AD for therapeutic targets.
    DOI:  https://doi.org/10.14336/AD.2025.1046
  3. Commun Med (Lond). 2025 Dec 20.
    Oral short-chain fatty acid-producing bacteria may be associated with biological age and cognition among the oldest old.
    Tim Wehnes, Weilan Wang, Jian Hua Tay, Lihuan Guan, Lei Feng, Chun Man Roger Ho, Tze Pin Ng, Brian K Kennedy, Ashok Venkitaraman, Woon-Puay Koh, Yap Seng Chong, Andrea B Maier.
       BACKGROUND: Biological age derived from DNA methylation (mAge) reflects aging-related physiological changes and the risk of age-related diseases. However, the association between oral microbiome and mAge remains unclear.
    METHODS: We examined associations between mAge, physical and cognitive function, and the oral microbiome in 311 community-dwelling, predominantly Chinese adults aged 85 years or older. Oral microbial composition was assessed using 16S rRNA sequencing, and mAge was estimated using four established epigenetic clocks: HorvathAge, HannumAge, PhenoAge, and GrimAge.
    RESULTS: In this cohort (median chronological age = 88.6 years; median DNA methylation-based biological age = 81.4 years), individuals with lower mAge deviation, corresponding to a younger biological age, exhibit lower oral microbial alpha diversity based on Simpson's index. While no taxa differences reach significance after correction for multiple testing, several short-chain fatty acid-producing genera, such as Prevotella_7 and Veillonella, show nominal associations with both mAge deviation and methylation at aging-related CpG sites, particularly in neurologically relevant genes. Higher abundance of Prevotella_7 species is associated with better cognitive performance (Mini-Mental State Examination), whereas Alloprevotella is linked to poorer cognition.
    CONCLUSION: Our findings highlight that, as far as we aware, previously unrecognized oral microbiome composition links to lower mAge deviation and better cognitive function among the oldest-old, suggesting a potential role of the oral microbiome in promoting healthy aging and informing future mechanistic investigations.
    DOI:  https://doi.org/10.1038/s43856-025-01288-6
  4. Biochemistry (Mosc). 2025 Dec;90(12): 2027-2040
    Mitochondria in Developing Brain: Contribution of Deviations to Higher Susceptibility to Neurodegeneration in Latter Periods of Life.
    Natalia A Stefanova, Natalia A Muraleva, Diana V Sityaeva, Mikhail A Tyumentsev, Nataliya G Kolosova.
      It has been proven that the preclinical period of the sporadic (>95% of cases) form of Alzheimer's disease (AD) can last for decades, but the question of when the disease begins to develop and what contributes to it remains open. It is hypothesized that vulnerabilities to AD may be influenced by anatomical and functional brain parameters formed early in life. This is supported by our research on the senescence-accelerated OXYS rats - a unique model of AD. The delayed brain maturation observed in these rats is associated with insufficient glial support, a key regulator of neural network function, and the development of AD signs in the OXYS rats is preceded and accompanied by the mitochondrial dysfunction. This raises the question of whether the structural and functional features of mitochondria could influence brain maturation and thus determine predisposition to the later development of AD signs. In this study, we compared mitochondrial biogenesis, their trafficking, and structural state in the neuronal cell bodies, axonal and dendritic processes, as well as activity of the mitochondrial dynamics processes in the prefrontal cortex and hippocampus of OXYS and Wistar rats (control) during the period of brain maturation completion (from birth to 20 days of age). Changes in the number and ultrastructural parameters of mitochondria were compared with the parameters of dynamics processes, assessed by the frequency of mitochondria undergoing fusion or fission, the content of the key biogenesis protein PGC-1α, and proteins mediating mitochondrial dynamics (mitofusins Mfn1 and Mfn2, dynamin-1-like protein DRP1). In OXYS rats, deviations in formation of the mitochondrial apparatus in the early postnatal period were identified, which may contribute to the delayed brain maturation of these rats, promote mitochondrial dysfunction, reduce synaptic density, and ultimately lead to the neuronal death and development of the early neurodegenerative changes.
    Keywords:  Alzheimer’s disease; early postnatal period; mitochondria; neurodegeneration; senescence-accelerated OXYS rats
    DOI:  https://doi.org/10.1134/S0006297925602874
  5. J Gastroenterol. 2025 Dec 23.
    Growth differentiation factor 15: from stress response to clinical utility in chronic liver diseases.
    Yuta Myojin, Hayato Hikita.
      The clinical landscape of chronic liver disease has changed with effective antiviral therapies, enabling the eradication of hepatitis C virus and the durable suppression of hepatitis B virus replication. Despite these advances, patients remain at risk for hepatocellular carcinoma (HCC) and other liver-related complications, but the growing burden of metabolic dysfunction-associated steatotic liver disease (MASLD) has created new challenges for clinical practice. These trends emphasize the need for reliable, noninvasive biomarkers that can stratify risk and guide long-term management across diverse etiologies. Growth differentiation factor 15 (GDF15), a stress-inducible cytokine, has attracted increasing interest as a promising biomarker. Its expression is induced by metabolic, oxidative, and inflammatory stress, and circulating levels increase with disease progression. Elevated serum GDF15 is consistently associated with fibrosis severity, HCC risk, hepatic decompensation, and mortality. Importantly, GDF15 is not merely a surrogate of fibrosis; rather, it integrates hepatocellular and stromal stress pathways and captures residual risk beyond fibrosis stage, liver function scores, and conventional biomarkers. In addition to its prognostic association, GDF15 has diverse biological effects. It may act as a protective response by limiting inflammation and cellular injury; yet, in other contexts, it contributes to fibrogenesis, tumor progression, immunosuppression, and cachexia. These dual roles highlight both the potential and the complexity of targeting GDF15 in therapeutic strategies. Collectively, the results of the current study indicate that GDF15 represents a promising biomarker in chronic hepatic diseases and is clinically independent of hepatic fibrosis. Further work is needed to clarify the underlying mechanisms, validate the prognostic utility, and determine whether GDF15 can be developed as a therapeutic target within precision medicine approaches.
    Keywords:  Biomarker; Hepatic decompensation; Liver cancer
    DOI:  https://doi.org/10.1007/s00535-025-02336-7
  6. Actas Esp Psiquiatr. 2025 Dec;53(6): 1252-1264
    High-Frequency rTMS can Improve Depressive Symptoms by Promoting Mitochondrial Fusion.
    Jingmei Song, Yaru Wang, Simeng Li, Jingyu Yuan, Zhenhui Zhang, Yifeng Pan, Jing Lu, Yuyan Zhang.
       BACKGROUND: Depression is a common and highly prevalent disabling mental disorder. Recent clinical data have shown that repetitive transcranial magnetic stimulation (rTMS) effectively improves depressive symptoms. Mitochondrial quality control (MQC) plays a central role in various psychiatric disorders. However, the relationship between the therapeutic mechanisms underlying rTMS and MQC remains unclear. This study aimed to evaluate the therapeutic effect of rTMS on depression and to investigate the relationship between rTMS and MQC.
    METHODS: A depression model was established using chronic unpredictable mild stress (CUMS). The rTMS treatment protocol was administered daily for 4 weeks at a frequency of 10 Hz (17 trains of 4 s each, with 15 s intervals), totaling 1000 pulses per day. Each session involved 10 s of stimulation followed by 50 s of rest and was divided into four groups: control, CUMS, CUMS + 10 Hz rTMS, and fluoxetine (FlX)-treated groups (six mice in each group). In this study, we used the open field test (OFT), tail suspension test (TST), sucrose preference test (SPT), and forced swimming test (FST) to assess depression in mice; immunohistochemical staining to observe changes in the prefrontal cortex (PFC), hippocampal neurons, and glial cells; and transmission electron microscopy to detect changes in mitochondrial morphology in the hippocampus.
    RESULTS: Our findings suggest that mitochondrial pre-autophagy increased after treatment (LC3Ⅰ/II, F = 34.31, p < 0.0001; FIS1, F = 6.666, p = 0.0272), hippocampal mitochondrial fusion was enhanced after treatment (NeuN, p < 0.0001; c-Fos, p < 0.001; MFN1, p = 0.0006), and that treatment significantly improved the depression-like behavior of mice in the SPT (p = 0.0024) and FST (p = 0.0025).
    CONCLUSION: The present study demonstrates that rTMS improves depression-like behavior in mice by promoting mitochondrial fusion and enhancing autophagy.
    DOI:  https://doi.org/10.62641/aep.v53i6.1934
  7. Expert Rev Mol Diagn. 2025 Dec 22.
    Identifying sex-specific biomarkers for intrinsic capacity decline in the aging population.
    Lv-Tao Zeng, Ya-Qing Ma, Hong-Lei Liu, Jian-Ping Cai.
       BACKGROUND: Intrinsic capacity (IC) decline is a key marker of aging-related functional loss, yet sex-specific biomarkers remain poorly characterized. This cross-sectional study of 1014 community-dwelling older adults investigated the associative strength and potential statistical intermediaries of insulin-like growth factor binding protein 2 (IGFBP2) and growth differentiation factor 15 (GDF-15) in IC impairment, with sex-stratified analyses.
    RESEARCH DESIGN AND METHODS: Dose-response relationships were assessed using restricted cubic splines. Multivariable logistic regression evaluated independent associations after adjusting for covariates. Mediation analysis explored roles of renal, muscular, metabolic, and oxidative stress indicators.
    RESULTS: IC impairment was associated with higher IGFBP2 and GDF-15 (all p < 0.001). In males, IGFBP2 showed a reverse L-shaped association (inflection at 310 ng/mL; AUC = 0.75), partially explained by renal function (β2-MG), muscle damage (CK, LDH), oxidative stress (SOD), and nutrition (ALB), with 11.02% mediation. In females, GDF-15 had a nonlinear relationship (inflection at 1.99 ng/mL; AUC = 0.76), attributable in part to glucose (FBG), lipids (FFA), and renal function (BUN), accounting for 19.8% of the effect. Fully adjusted ORs were 2.41 (IGFBP2 in males) and 4.27 (GDF-15 in females), both p < 0.001.
    CONCLUSION: IGFBP2 and GDF-15 are sex-specific biomarkers for IC decline, operating through distinct pathways, and may aid early screening and targeted interventions.
    Keywords:  GDF-15; IGFBP2; Intrinsic capacity; aging; biomarkers
    DOI:  https://doi.org/10.1080/14737159.2025.2606411
  8. Lancet Healthy Longev. 2025 Dec 22. pii: S2666-7568(25)00122-9. [Epub ahead of print] 100803
    Menopause hormone therapy and risk of mild cognitive impairment or dementia: a systematic review and meta-analysis.
    Melissa Melville, Lexi He, Roopal Desai, Primrose Nyamayaro, Chris Fox, Kavita U Kothari, Patrick Condron, Miao Miao, Martha Hickey, Aimee Spector.
       BACKGROUND: Globally, dementia disproportionately affects women. Changes in circulating sex steroids over the menopause transition might contribute to this sex difference. Menopause hormone therapy (MHT) is recommended by the UK National Institute for Health and Care Excellence to manage menopausal symptoms, but whether MHT use affects dementia risk and how this association might vary by age at menopause is unclear. We aimed to assess whether MHT (vs no MHT) affects the risk of mild cognitive impairment or dementia in peri-menopausal or post-menopausal women, including those with premature ovarian insufficiency or early menopause (with normal cognition or mild cognitive impairment), and whether MHT type, duration, or age at initiation influence this risk.
    METHODS: We systematically searched MEDLINE via OVID, Embase via Elsevier, Cochrane via OVID, and PsycINFO via OVID for systematic reviews published between Jan 1, 2000, and Dec 19, 2024. As no existing review met our quality or scope criteria, we proceeded to conduct a systematic review and meta-analysis of primary studies published from Jan 1, 2000, to Oct 20, 2025. Eligible primary studies included randomised controlled trials (RCTs), non-randomised intervention studies, and prospective observational studies examining the association between MHT-including oestrogen-only MHT, combined MHT, testosterone, and tibolone-and incident mild cognitive impairment or dementia. Two reviewers independently screened studies, extracted data, and assessed risk of bias using RoB 2 and ROBINS-E, with certainty of evidence rated using GRADE. Meta-analyses pooled relative risk estimates in a random-effects model. The protocol was preregistered on PROSPERO (CRD42025639384).
    FINDINGS: Of 5914 records, ten studies (one RCT and nine observational studies) with a total of 1 016 055 participants were included. Certainty of evidence ranged from moderate to very low. No included studies examined testosterone or use in premature ovarian insufficiency. No significant association was found between MHT use and risk of mild cognitive impairment or dementia. Subgroup analyses by timing, duration, and type of MHT showed no significant effects.
    INTERPRETATION: This review found no evidence that MHT use either increases or decreases the risk of dementia in post-menopausal women. This reinforces current clinical guidance, that MHT prescription should be based on other perceived benefits and risks and not for dementia prevention. High-quality, long-term studies are needed to clarify the role of MHT and dementia risk, particularly regarding formulation, dose, route, timing, and duration of treatment, with a focus on women with premature ovarian insufficiency, early menopause, or mild cognitive impairment.
    FUNDING: The Public Health Agency of Canada.
    DOI:  https://doi.org/10.1016/j.lanhl.2025.100803
  9. Adv Biol (Weinh). 2025 Dec 22. e00410
    Synergistic Roles of FAHD-1 and PYC-1 in Mitochondrial Function, Behavior, and Longevity in C. elegans.
    Riccardo Giaquinta, Andreas Andric, Matthias Scheppach, Alexander K H Weiss.
      Mitochondrial metabolism plays a central role in organismal physiology and aging. In Caenorhabditis elegans, FAHD-1 (oxaloacetate decarboxylase) and PYC-1 (pyruvate carboxylase) catalyze opposing reactions that influence oxaloacetate homeostasis within the tricarboxylic acid cycle. To dissect their functional interplay, we analyzed single- and double-knockout strains generated by CRISPR/Cas9 alongside the classical allele. Fahd-1 mutants exhibit impaired mitochondrial respiration, reduced motility, and early egg-laying onset, whereas pyc-1 mutants display increased locomotion and enhanced metabolic flexibility. Paradoxically, although each single mutantion extended lifespan, combining them restored wild-type lifespan and partially normalized respiratory function, suggesting a compensatory interaction. These findings establish FAHD-1 and PYC-1 as antagonistic mitochondrial enzymes whose balance governs locomotion, reproduction, and lifespan in C. elegans, providing a conceptual framework for conserved links between mitochondrial metabolism and aging.
    Keywords:  caenorhabditis elegans; cell biology; citric acid cycle; mitochondrion; motility
    DOI:  https://doi.org/10.1002/adbi.202500410
  10. NPJ Aging. 2025 Dec 26.
    Reversal of proteomic aging with exercise-results from the UK biobank and a 12-week intervention study.
    Sindre Lee-Ødegård, M Austin Argentieri, Frode Norheim, Christian Andre Drevon, Kåre Inge Birkeland.
      Biological aging varies between individuals and may be influenced by health behaviors. Using data from 45,438 UK Biobank participants, we found that a higher proteomic aging score (ProtAgeGap) was linked to lower physical activity and increased risk of type 2 diabetes. The UK Biobank cohort included both men and women. In a 12-week supervised exercise study (MyoGlu) in 26 men, ProtAgeGap decreased by the equivalent of 10 months. While most of the 204 proteins in the score remained stable, some, like CLEC14A, changed with exercise and were linked to improved insulin sensitivity. Transcriptomic data from muscle and fat tissue supported these protein-level changes, highlighting pathways, such as PI3K-Akt and MAPk signaling, involved in tissue remodeling and metabolism. Our findings suggest that while proteomic aging is mostly stable, it can be modestly reversed by exercise. Specific proteins within the signature may act as sensitive indicators of metabolic adaptation, supporting the idea that proteomic aging is a modifiable marker linked to lifestyle and disease risk. Clinical trial number: clinicaltrials.gov: NCT01803568 registered 2013-02-26.
    DOI:  https://doi.org/10.1038/s41514-025-00318-w
  11. Biochemistry (Mosc). 2025 Dec;90(12): 1862-1882
    Suppressing Mitochondrial ROS Production is Beneficial in Multiple Preclinical Models of Human Disease.
    Martin D Brand.
      I discuss the therapeutic potential of site-specific suppressors of the production of mitochondrial reactive oxygen species (ROS). The best-defined suppressors are S1QELs (targeting site IQ in complex I) and S3QELs (targeting site IIIQo in complex III). They prevent ROS formation at source without affecting oxidative phosphorylation. The antidiabetic drug imeglimin and the anti-xerostomia and antischistosomal anethole dithiolethiones also have S1QEL activity, although how much this contributes to their clinical effects needs further study. Suppressing mitochondrial ROS production has therapeutic potential in many diseases. S1QELs and imeglimin improve glucose tolerance, insulin sensitivity, and decrease hepatic steatosis in models of diabetes and obesity. S1QELs and S3QELs protect against age-related cardiac decline, atrial fibrillation and hypertension. They reduce inflammatory cytokines and oxidative stress in macrophages and other cells. They inhibit cancer cell proliferation and tumour growth. In neurological diseases, S1QELs protect against noise-induced hearing loss. S1QELs protect against cardiac and hepatic damage during ischemia-reperfusion. S1QELs and S3QELs extend lifespan in model organisms and S3QELs protect against aging-related intestinal barrier dysfunction. Suppressors mitigate drug-induced toxicities (e.g., acetaminophen, cisplatin) and the effects of environmental stressors. In exocrinopathy, anethole dithiolethione alleviates symptoms of dry mouth and dry eye. Suppressors of mitochondrial ROS production show promise in treating a wide range of diseases driven by mitochondrial oxidative stress. Their mechanism-based specificity offers advantages over traditional antioxidants, with potential applications in metabolic, cardiovascular, inflammatory, neurological, and aging-related diseases. Further research is needed to fully explore their clinical efficacy.
    Keywords:  ROS; S1QEL; S3QEL; acetaminophen; aging; anethole dithiolethione; cancer; cardiomyopathy; cisplatin; imeglimin; inflammation; ischemia/reperfusion injury; mitochondria; noise-induced hearing loss; type 2 diabetes
    DOI:  https://doi.org/10.1134/S0006297925602527
  12. J Pharmacol Exp Ther. 2025 Dec 01. pii: S0022-3565(25)40300-0. [Epub ahead of print]393(1): 103787
    An orally active estrogen receptor-related receptor agonist, SLU-PP-915, enhances aerobic exercise capacity.
    Cyrielle Billon, Kevin Appourchaux, Isabelle Côté, Thomas P Burris.
      Estrogen receptor-related receptors (ERRα, ERRβ, and ERRγ) are orphan nuclear receptors that regulate genes involved in mitochondrial biogenesis, oxidative phosphorylation, fatty acid oxidation, and the Krebs cycle. ERRs are essential for skeletal muscle adaptation to aerobic exercise and represent promising targets for exercise mimetic therapeutics. We previously developed an ERR pan-agonist, SLU-PP-332 (332), which improves aerobic performance in mice but lacks oral bioavailability. Here, we characterize SLU-PP-915 (915), a chemically distinct ERR pan-agonist that is orally bioavailable and exhibits potent in vivo exercise mimetic activity. Compound 915 enhances aerobic exercise performance (distance and duration) to a similar extent as 332 when administered intraperitoneally and maintains comparable efficacy when administered orally, adjusted for systemic exposure. Both compounds robustly induce the expression of DNA damage-inducible transcript 4 (Ddit4), a gene induced by acute aerobic exercise, with levels matching or exceeding levels induced by treadmill running, depending on the muscle examined. Notably, 915 synergizes with exercise training to further enhance Ddit4 and mitochondrial gene expression. These findings position orally active ERR agonists such as 915 as promising agents for the treatment of metabolic disorders (eg, obesity, type 2 diabetes, and metabolic disease-associated steatohepatitis), cardiovascular disease (heart failure), and muscle-related pathologies, including sarcopenia and muscular dystrophies. SLU-PP-915 offers a valuable chemical tool for exploring the chronic therapeutic potential of ERR activation. SIGNIFICANCE STATEMENT: The nuclear receptor estrogen receptor-related receptor plays an important role in driving the physiological adaptations to exercise. The article describes the ability of a pan-estrogen receptor-related receptor agonist SLU-PP-915, which also displays oral bioavailability, to enhance exercise capacity.
    Keywords:  Aerobic exercise; Energetics; Exercise; Exercise mimetic; Nuclear receptor; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.jpet.2025.103787
  13. Biochem Biophys Rep. 2026 Mar;45 102399
    Curcumin reprograms metabolic pathways and MAPK signaling to exert antidepressant effects.
    Sijin Kong, Lijin Wang, ZiXuan Ren.
       Background: Depression is a prevalent and debilitating mental disorder with limited treatment options. Curcumin, a natural compound with neuroprotective and anti-inflammatory properties, has shown potential antidepressant effects, though the underlying mechanisms remain incompletely understood.
    Methods and results: In this study, we investigated the therapeutic effects and molecular mechanisms of curcumin in a chronic unpredictable mild stress (CUMS)-induced rat model of depression. Behavioral assessments, including the sucrose preference test, forced swim test, and open field test, demonstrated that curcumin (50 and 100 mg/kg, orally administered for 21 days) alleviated CUMS-induced anhedonia, behavioral despair, and anxiety-like behaviors, in a dose-dependent manner, with the 100 mg/kg dose exhibiting superior efficacy. Metabolomic profiling of the prefrontal cortex revealed significant metabolic disturbances in CUMS rats, particularly in starch and sucrose metabolism, which were progressively restored by curcumin. Functional enrichment analysis highlighted modulation of neuroinflammation, bioenergetic homeostasis, and signal transduction pathways as key biological processes associated with curcumin's effects. Integrated multi-omics and machine learning approaches identified the MAPK signaling pathway as a central regulatory node. qPCR validation confirmed that curcumin normalized the expression of key MAPK-related genes, including BDNF, EGFR, ERK2, JUN, RAF1, and TNF, with high-dose curcumin consistently showing the most pronounced therapeutic effects.
    Conclusion: Our findings demonstrate that curcumin exerts potent antidepressant effects through multi-target mechanisms involving metabolic reprogramming and coordinated regulation of the MAPK signaling pathway. This study provides novel mechanistic insights into curcumin's polypharmacological actions, supporting its potential as a multi-modal therapeutic agent for depression by simultaneously modulating neurotrophic support, inflammatory responses, and intracellular signaling cascades.
    Keywords:  Curcumin; MAPK signaling; Machine learning; Major depressive disorder; Metabolomics
    DOI:  https://doi.org/10.1016/j.bbrep.2025.102399
  14. J Sport Health Sci. 2025 Dec 18. pii: S2095-2546(25)00121-8. [Epub ahead of print] 101113
    Exercise-induced β-hydroxybutyrate contributes to cognitive improvement in aging mice.
    Lian Wang, Liwei Mao, Danlin Zhu, Ke Li, Haoyang Gao, Muge Zhou, Jiabin Wu, Dan Yang, Ze Wang, Wenhong Wang, Yifan Guo, Yingying Xu, Peijie Chen, Weihua Xiao.
       BACKGROUND: Aging is a major contributor to cognitive decline and neurodegeneration, yet effective interventions to counteract aging-related neuronal dysfunction remain limited. β-hydroxybutyrate (β-HB), a ketone body elevated during fasting or aerobic exercise, functions as both an energy substrate and a signaling metabolite.
    METHODS: We assessed the effects of exercise-induced and exogenously supplemented β-HB on cognitive performance in aging mice. To examine the role of endogenous β-HB metabolism, we used 3-hydroxybutyrate dehydrogenase 1 (BDH1) knockout mice. In vitro, we investigated the impact of G protein-coupled receptor 109A (GPR109A) knockdown on β-HB-mediated activation of peroxisome proliferator-activated receptor gamma (PPARγ) and downstream pathways.
    RESULTS: Exercise elevated circulating β-HB levels and improved cognitive outcomes in aging mice. Exogenous β-HB supplementation mimicked these benefits. Loss of BDH1 impaired endogenous β-HB production and attenuated both exercise- and β-HB-induced cognitive improvements. In vitro, GPR109A knockdown suppressed β-HB-driven activation of PPARγ and downstream neuroprotective pathways linked to inflammation and oxidative stress.
    CONCLUSION: These findings identify the β-HB/GPR109A-PPARγ axis as a key mediator of exercise-induced cognitive enhancement in aging. β-HB emerges as a potential therapeutic candidate to mitigate brain aging and cognitive decline.
    Keywords:  BDH1; Exercise; GPR109A; PPARγ; β-hydroxybutyrate
    DOI:  https://doi.org/10.1016/j.jshs.2025.101113
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