bims-cesirm 2025-09-07 papers

bims-cesirm

Biomed News

on Cell Signaling mediated regulation of metabolism

Issue of 2025–09–07
nine papers selected by
Tigist Tamir, University of North Carolina

An emerging role for cysteine-mediated redox signaling in aging.
The nutrient sensing for whole-body homeostasis: beyond the cellular level.
FGF21 and GDF15 Act Synergistically to Regulate Systemic Metabolic Homeostasis in Mice Lacking OPA1 in Thermogenic Adipocytes.
Mapping the FOXA1 Interactome in ER+ Breast Cancer Cells using Proximity Labeling Reveals Novel Interactions with the Orphan Nuclear Receptor NR2C2.
Metabolic dysfunction-associated steatohepatitis reduces hepatic H2S-producing enzymes altering persulfidome composition.
Metastatic breast cancer cells are vulnerable to fatty acid oxidation inhibition through DDX3-DRP1-mediated mitochondrial plasticity.
β-hydroxybutyrate dehydrogenase promotes pancreatic cancer cell proliferation through regulation of the NAD+/NADH balance and mitochondrial acetylation.
Impaired xCT-mediated cystine uptake drives serine and proline metabolic reprogramming and mitochondrial fission in skeletal muscle cells.
Ceramide-induced Endoplasmic Reticulum Stress as a Targetable Vulnerability in Endocrine Therapy-Resistant Breast Cancer.

Redox Biol. 2025 Aug 29. pii: S2213-2317(25)00365-9. [Epub ahead of print]86 103852

An emerging role for cysteine-mediated redox signaling in aging.

Jin Meng.

  Reactive oxygen species (ROS) and hydrogen sulfide (H2S) are naturally produced during metabolic processes. At physiological levels, they act as oxidation-reduction (redox) signaling molecules and regulate a myriad of cellular processes. Redox signaling occurs largely through rapid and reversible oxidation of reactive cysteine residues in target proteins, leading to changes in protein ligand binding affinity, subcellular localization, and function. Recent studies have demonstrated that ROS and H2S play an essential role in various longevity models, and that a mild increase in ROS or H2S levels is sufficient to extend lifespan in model organisms. Meanwhile, the number of aging-related proteins that are modulated by ROS- or H2S-mediated post-translational modification is constantly growing. In this review, we aim to summarize key results that support cysteine-based redox regulation of organismal aging and lifespan. Better understanding of how mechanistically redox signaling controls aging will provide new perspectives for the development of targeted anti-aging strategies.

Keywords:  Aging; H(2)S; Post-translational modification of cysteine residues; ROS; Redox regulation

DOI:  https://doi.org/10.1016/j.redox.2025.103852
Mol Cells. 2025 Aug 29. pii: S1016-8478(25)00095-0. [Epub ahead of print] 100271

The nutrient sensing for whole-body homeostasis: beyond the cellular level.

Gahbien Lee, Jiyeon Lee, Greg S B Suh, Yangkyun Oh.

  Systemic nutrient sensing is a fundamental process that aligns nutrient availability with an organism's metabolic demands. This mini-review explores nutrient sensors in the intestine, pancreas, portal vein, and the brain-organs that detect and convey nutrient status to other tissues via neuronal and hormonal signaling. Unlike oral taste receptors that sense external nutrient inputs, these nutrient sensors monitor post-ingestive levels of macronutrients (carbohydrates, proteins, and lipids) and micronutrients (vitamins and essential trace elements such as calcium, magnesium, and zinc) within the body. We describe the specific mechanisms by which each organ discerns fluctuations in nutrient concentration and discuss how these signals integrate into endocrine and neural circuits to maintain whole-body nutrient balance. Finally, by comparing mammalian and invertebrate models such as Drosophila, we offer a comprehensive perspective on how organ-level nutrient sensing upholds metabolic homeostasis across diverse species.

Keywords:  Nutrient sensing; gut–brain communication; metabolic homeostasis; systemic nutrient sensors

DOI:  https://doi.org/10.1016/j.mocell.2025.100271
Obesity (Silver Spring). 2025 Sep 02.

FGF21 and GDF15 Act Synergistically to Regulate Systemic Metabolic Homeostasis in Mice Lacking OPA1 in Thermogenic Adipocytes.

Joshua Peterson, Jayashree Jena, Ayushi Sood, Shelly Roitershtein, David Smith, Renata O Pereira.

   OBJECTIVE: Our previous studies showed that mice lacking the mitochondrial fusion protein optic atrophy 1 (OPA1 BKO) in brown adipose tissue (BAT) have high metabolic rates and are resistant to diet-induced obesity (DIO) via effects partially mediated by independent actions of fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) secretion from BAT. We examined whether FGF21 and GDF15 act synergistically, contributing to the systemic metabolic adaptations reported in OPA1 BKO mice.
METHODS: We generated mice simultaneously lacking the Opa1, Fgf21, and Gdf15 genes in thermogenic adipocytes (TKO) and assessed energy homeostasis and glucose metabolism after regular chow or high-fat diet feeding.
RESULTS: Young TKO mice fed regular chow had impaired glucose tolerance, while insulin sensitivity was unchanged. Notably, combined Fgf21 and Gdf15 deletion in OPA1 BKO significantly blunted the resistance to DIO and insulin resistance observed in OPA1 BKO mice.
CONCLUSIONS: FGF21 and GDF15 act synergistically to maintain glucose homeostasis and promote resistance to DIO in mice lacking OPA1 in BAT, highlighting the potential of combined therapies using FGF21 and GDF15 for the treatment of metabolic disorders.

Keywords:  Brown Adipose Tissue; FGF21; GDF15; Mitochondrial Stress; Obesity

DOI:  https://doi.org/10.1002/oby.70004
Mol Cancer Res. 2025 Aug 28.

Mapping the FOXA1 Interactome in ER+ Breast Cancer Cells using Proximity Labeling Reveals Novel Interactions with the Orphan Nuclear Receptor NR2C2.

Rosemary N Plagens, Carla S Rodriquez Tirado, Shen Li, Natalia Maldonado-Vazquez, Ingrid M Montes-Rodriguez, Julie Dutil, Christine A Mills, Laura E Herring, Hector L Franco.

FOXA1 is a pioneer transcription factor essential for chromatin accessibility and transcriptional regulation in hormone-driven cancers. In breast cancer, FOXA1 plays a central role in facilitating nuclear receptor binding, reprogramming enhancer landscapes, and promoting transcriptional changes associated with therapy resistance. While FOXA1's function has been primarily studied in the context of estrogen receptor-α (ER), its broader protein interaction network remains incompletely defined. Here, we systematically map FOXA1-interacting proteins in ER-positive breast cancer cells using proximity-dependent biotin labeling (miniTurbo) combined with quantitative LC-MS/MS proteomics. We engineered MCF-7 cell lines stably expressing miniTurbo-tagged FOXA1 at either the N-terminus or C-terminus to ensure comprehensive coverage of interaction interfaces. This approach recovered known FOXA1 partners, including AR, MLL3, YAP1, and GATA3, and identified 157 previously unreported FOXA1 interactors. Notably, 42 of these novel partners, including NR2C2, were significantly associated with poor relapse-free survival in ER+ breast cancer patients. To demonstrate the utility of this resource, we characterized the FOXA1-NR2C2 interaction in depth. Integrating ChIP-seq and RNA-seq, we show that FOXA1 and NR2C2 co-occupy a subset of genomic regions and drive co-regulated transcriptional programs involved in tumor progression. Our study reveals an expanded FOXA1 interactome and new insights into its functional network in breast cancer, providing candidate proteins for further exploration as biomarkers or therapeutic targets. Implications: These findings expand the FOXA1 interactome in breast cancer and uncover new candidate proteins with potential as biomarkers and therapeutic targets in hormone-driven tumors.

DOI: https://doi.org/10.1158/1541-7786.MCR-25-0085
Redox Biol. 2025 Aug 05. pii: S2213-2317(25)00322-2. [Epub ahead of print]86 103809

Metabolic dysfunction-associated steatohepatitis reduces hepatic H2S-producing enzymes altering persulfidome composition.

Tzu Keng Shen, Thibaut Vignane, Eduardo H Gilglioni, Leonardo Traini, Elisavet Kalaitsidou, Pierre Conan, Ao Li, Wadsen St-Pierre-Wijckmans, Jose M Herranz, Bernat Elvira, Lukas Otero Sanchez, Eric Trépo, Leo Deelman, Wei Wu, Milos R Filipovic, Joris Messens, Daria Ezeriņa, Esteban N Gurzov.

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive disease driven by obesity-related hepatic inflammation and oxidative stress. Recently, cysteine persulfidation (PSSH), a protective post-translational modification by hydrogen sulfide (H2S), was established to play a role in redox regulation. Despite the role of the liver in H2S metabolism, the function of PSSH in MASH remains underexplored. We demonstrated that H2S-producing enzymes are downregulated in both human and mouse livers with steatosis and fibrosis, resulting in a decline in global PSSH levels. Dimedone-switch mass spectrometry in dietary mouse models of distinct obesity-associated liver disease stages revealed dysregulated PSSH on specific proteins. Surprisingly, increased hepatic PSSH levels of protein tyrosine phosphatases and redox regulators were found in advanced disease stages, suggesting a targeted adaptive response to oxidative stress. Overall, our findings demonstrated that impaired H2S production disrupts protective PSSH networks in MASH. However, selective PSSH preservation on redox-sensitive proteins may represent a compensatory mechanism, underscoring the therapeutic potential of persulfidation in restoring redox homeostasis during obesity-associated chronic liver disease.

DOI: https://doi.org/10.1016/j.redox.2025.103809
Redox Biol. 2025 Aug 26. pii: S2213-2317(25)00358-1. [Epub ahead of print]86 103845

Metastatic breast cancer cells are vulnerable to fatty acid oxidation inhibition through DDX3-DRP1-mediated mitochondrial plasticity.

Wen-Jing Hsu, Ming-Chien Hsu, Cheng-Ying Chu, Yu-Cheng Lee, Ching-Chieh Yang, Zei-Wei Liu, Chi-Ching Lee, Yang-Sen Lin, Cheng-Wei Lin.

  Metastatic tumor cells exhibit distinct metabolic flexibility in overcoming different microenvironmental obstacles and thriving in a secondary organ; thus, metabolic vulnerabilities can potentially be targeted. It was reported that mitochondrial biogenesis and dynamics play crucial roles in disseminated tumor cells satisfying their energy demands and metabolic plasticity. However, the detailed molecular mechanism by which mitochondrial dynamics promotes tumor metastasis is still unclear. Herein, we identified that metastatic breast cancer cells exhibited increased lipid contents in mitochondria and promoted a metabolic shift towards fatty acid oxidation (FAO). The increased FAO was accompanied by promotion of mitochondrial fission. Mechanistically, we found that upregulation of DEAD-box polypeptide 3, X-linked (DDX3) promoted mitochondrial fission and facilitated FAO. Suppression of DDX3 diminished FAO and elicited mitochondrial oxidative stress in metastatic tumor cells. Moreover, DDX3 mediated dynamin-related protein 1 (DRP1) phosphorylation at S616 through collaborating with cyclin-dependent kinase 1 (CDK1). Inhibition of the DDX3-DRP1-CDK1 axis reduced cancer stemness properties and tumor metastasis. Our findings indicate that DDX3 modulates mitochondrial plasticity to drive metabolic adaptation in breast tumor metastasis. DDX3 provides a potential diagnostic biomarker and therapeutic vulnerability through which cancer metabolism can be targeted.

Keywords:  DDX3; DRP1; FAO; Mitochondrial fission; Tumor metastasis

DOI:  https://doi.org/10.1016/j.redox.2025.103845
J Biol Chem. 2025 Aug 28. pii: S0021-9258(25)02488-3. [Epub ahead of print] 110636

β-hydroxybutyrate dehydrogenase promotes pancreatic cancer cell proliferation through regulation of the NAD+/NADH balance and mitochondrial acetylation.

Xiujuan Wei, Chengkai Zhang, Xiaoguang Zheng, Kexin Pan, Xiaojun Ren, Xiaoting Lou, Zhengquan Yang, Ting Fu, Hezhi Fang, Jianxin Lu.

  Ketone bodies are a key alternative energy source during carbohydrate deficiency. In addition to their metabolic function, they regulate essential cellular processes, including metabolism, signal transduction, and protein post-translational modifications (PTMs). However, the role of ketone body metabolism in tumorigenesis remains poorly understood. Here, we demonstrate that ketone body synthesis metabolism is activated in pancreatic cancer, while exogenous ketone supplementation does not affect PDAC cell proliferation. Moreover, we observe a significant upregulation of β-Hydroxybutyrate dehydrogenase (BDH1), a key enzyme in ketone body metabolism, in human pancreatic ductal adenocarcinoma (PDAC) tissues compared to adjacent normal pancreatic tissues. BDH1 promotes PDAC cell proliferation by maintaining mitochondrial acetylation levels through regulation of the intracellular NAD+/NADH ratio. These findings underscore the importance of ketone body metabolism in pancreatic cancer progression and highlight the regulatory role of BDH1 in maintaining cellular NAD+/NADH balance and mitochondrial acetylation.

Keywords:  BDH1; Ketone body; NAD(+)/NADH; Pancreatic Cancer; mitochondrial acetylation

DOI:  https://doi.org/10.1016/j.jbc.2025.110636
Redox Biol. 2025 Aug 21. pii: S2213-2317(25)00352-0. [Epub ahead of print]86 103839

Impaired xCT-mediated cystine uptake drives serine and proline metabolic reprogramming and mitochondrial fission in skeletal muscle cells.

Michel N Kanaan, Charbel Y Karam, Luke S Kennedy, Chantal A Pileggi, Lauren Hamilton, Miroslava Cuperlovic-Culf, Mary-Ellen Harper.

  Muscle satellite cell (MuSC) proliferation is tightly regulated by redox homeostasis and nutrient availability, which are often disrupted in muscular pathologies. Beyond its role in maintaining cellular redox homeostasis, this study identified a key metabolic role for cystine/glutamate antiporter xCT in proliferating MuSCs. We investigated the impact of impaired xCT-mediated cystine import in Slc7a11sut/sut MuSCs isolated from mice that harbor a mutation in the SLC7A11 gene, which encodes xCT. We used complementary approaches to study how disrupted cystine import affects glutathione (GSH) redox, cellular bioenergetics, mitochondrial dynamics, and metabolism. Oxygen consumption rates of Slc7a11sut/sut MuSCs were lower, indicative of compromised mitochondrial oxidative capacity. This was accompanied by a fragmented mitochondrial network associated with OPA1 cleavage and redox-sensitive DRP1 oligomerization. Metabolomic profiling revealed a distinct metabolic signature in Slc7a11sut/sut MuSCs, manifested by major differences in BCAAs, pyrimidines, cysteine, methionine, and GSH. Despite lower overall bioenergetic flux, stable-isotope tracing analyses (SITA) showed that xCT deficiency increased glucose uptake, channeling glucose-derived carbons into de novo serine biosynthesis to fuel cysteine production via the transsulfuration pathway, partially compensating for disrupted GSH redox. Furthermore, xCT deficiency triggered upregulated pyrroline-5-carboxylate synthase (P5CS)-mediated proline reductive biosynthesis. By directing glutamate into proline synthesis, MuSCs apparently downregulate oxidative phosphorylation (OXPHOS) and regulate intracellular glutamate levels in response to impaired cystine/glutamate antiporter function. Our findings highlight the roles of xCT in regulating redox balance and metabolic reprogramming in proliferating MuSCs, providing insights that may inform therapeutic strategies for muscular and redox-related pathologies.

Keywords:  Cysteine; Cystine/glutamate antiporter; Glycolysis; Metabolic reprogramming; Mitochondria; Myopathy; Oxidative phosphorylation; Proline; Skeletal muscle; Slc7a11; System Xc−; Transsulfuration pathway

DOI:  https://doi.org/10.1016/j.redox.2025.103839
bioRxiv. 2025 Aug 22. pii: 2025.08.18.670862. [Epub ahead of print]

Ceramide-induced Endoplasmic Reticulum Stress as a Targetable Vulnerability in Endocrine Therapy-Resistant Breast Cancer.

Purab Pal, Shweta Chitkara, Godwin K Sarpey, Fatimah Alani, Huiping Zhao, Malik Ata, Jun Qu, Rachel Schiff, Debra Tonetti, Geoffrey L Greene, Jonna Frasor, Gunes Ekin Atilla-Gokcumen, Jonathan L Coloff.

  Despite the success of endocrine therapy (ET) in treating hormone receptor-positive breast cancer, a significant proportion of patients relapse during or after treatment, making ET resistance a major clinical challenge. Previously we have shown that ET-resistant breast cancer cells exhibit reduced ceramide levels and an increased sensitivity to ceramide-induced cell death. Here, we demonstrate that ceramides induce a distinct transcriptional reprogramming in ET-resistant cells, characterized by upregulation of endoplasmic reticulum stress (EnRS) pathways. Ceramide-induced EnRS is PERK-dependent and functionally linked to cell death in multiple models of ET resistance. Using a photoactivatable ceramide probe, we identify TRAM1 as a functionally important ceramide-interacting protein (CIP) in ET-resistant cells that correlates with worse relapse-free survival and a more aggressive breast cancer phenotype in luminal breast cancer patients. Additionally, knockdown of TRAM1 phenocopies ceramide action in ET resistance, thereby suggesting its role in mediating ceramide-induced lethal actions in ET resistance. Together, our findings reveal that ET-resistant breast cancer cells are more sensitive to PERK-mediated EnRS as compared to their ET-sensitive counterparts. Ceramides can exploit this dependence by interacting with CIPs such as TRAM1, leading to PERK activation and consequential cell death preferentially in the ET-resistant breast cancer models.

Keywords:  Ceramide; Ceramide-interacting proteins; Endocrine therapy resistance; Endoplasmic reticulum stress; Luminal breast cancer; PERK; TRAM1

DOI:  https://doi.org/10.1101/2025.08.18.670862