bims-cesirm 2026-03-15 papers

bims-cesirm

Biomed News

on Cell Signaling mediated regulation of metabolism

Issue of 2026–03–15
nine papers selected by
Tigist Tamir, University of North Carolina

Global profiling of protein lactylation in pancreatic ductal adenocarcinoma.
Unveiling the hidden regulators: how post-translational modifications influence the progression and treatment of hepatocellular carcinoma.
Proteomics and Lipidomics Analysis Reveal That Membrane Remodeling and Extracellular Matrix Alterations Are Crucial for Cisplatin Resistance in Triple-Negative Breast Cancer.
Glucokinase Inactivation Reduces Lysophosphatidylcholine Accumulation to Alleviate High-Fat Diet-Induced Hepatic Steatosis.
Mitochondrial uncoupling inhibits serine catabolism via FTO activation in metastatic breast cancer.
NAD+ hydrolysis catalyzed by SelO is required for mitochondrial homeostasis.
Pyruvate metabolism enzyme Dlat induces mitochondria protein hyperacetylation to limit fatty acid oxidation in the HFpEF heart.
Cys340Ser Mutation Abolishing S-Nitrosylation Drives GRK2 Mitochondrial Localization and Dysfunction.
Succinylation: A Functional Nexus Between Metabolic Reprogramming and Epigenetic Modifications in Cancer.

Sci Rep. 2026 Mar 12.

Global profiling of protein lactylation in pancreatic ductal adenocarcinoma.

Daniela Toledo, Samuel Abidemi Oluwole, Solomon Owiredu, Grace Carr, Christian Agatemor.



Keywords:  Intellectual disability; Lactylation; Lactylome; Pancreatic cancer; Posttranslational modifications

DOI:  https://doi.org/10.1038/s41598-026-43771-7
Front Oncol. 2026 ;16 1726574

Unveiling the hidden regulators: how post-translational modifications influence the progression and treatment of hepatocellular carcinoma.

Shuaiyong Qi, Xiang Yong, Zhixian Ding, Mengxue Hu, Yafen Li, Lili Li, Huaiyuan Hu, Heng Tang.

  Hepatocellular carcinoma (HCC) is a common and aggressive primary liver cancer. Due to its high incidence and fatality rates, it poses a serious threat to global public health. Protein post-translational modifications (PTMs) are crucial regulatory mechanisms that occur after translation and fine-tune cellular functions. Common PTM types-including phosphorylation, ubiquitination, acetylation, methylation, glycosylation, ubiquitin-like modifications (such as UFMylation and SUMOylation), and Lactylation-affect protein activity, stability, subcellular localization, and interaction networks. These modifications dynamically regulate various biological processes in response to internal and external stimuli. Dysregulated PTMs have been intimately associated with the development, spread, and resistance to treatment of HCC in the setting of cancer. This review provides new insights into the molecular mechanisms underlying HCC by systematically examining the roles of PTMs. It also seeks to inform therapeutic strategies and improve diagnosis and prognostic assessment.

Keywords:  clinical translation; hepatocellular carcinoma; metabolic reprogramming; post-translational modifications; therapy

DOI:  https://doi.org/10.3389/fonc.2026.1726574
J Proteome Res. 2026 Mar 13.

Proteomics and Lipidomics Analysis Reveal That Membrane Remodeling and Extracellular Matrix Alterations Are Crucial for Cisplatin Resistance in Triple-Negative Breast Cancer.

Shashwati Parihari, Saheli Sarkar, Vidhi Vashishtha, Sanjeeva Srivastava.

  Cisplatin is a widely used chemotherapeutic agent for triple-negative breast cancer (TNBC), but resistance remains a major challenge. Understanding the molecular alterations driving this resistance is essential for identifying therapeutic targets. In this study, we employed an integrated proteomics and lipidomics approach to elucidate key pathways associated with cisplatin resistance. Employing high-resolution mass spectrometry, we conducted a comparative analysis between cisplatin-resistant (cisR) and cisplatin-sensitive (cisS) TNBC cell lines to discover resistance-associated alterations in protein and lipid expression. Proteomic analysis revealed overexpression of extracellular matrix (ECM) remodeling proteins, COL6A1, COL6A2, COL6A3, and VTN, that support epithelial-mesenchymal transition (EMT) and chemoresistance. Membrane-associated proteins such as TIMP2, MMP14, and APP were also elevated, indicating enhanced invasive and pro-survival signaling. Lipidomic alterations, including upregulation of FABP3, FABP4, LPL, and downregulation of PLA2G4A, indicated increased lipid uptake, metabolic rewiring, and membrane restructuring. Notably, elevated long-chain phosphatidylcholines and decreased sphingomyelins suggested increased membrane rigidity and reduced cisplatin permeability. Additionally, dysregulation of CDK activity through CCND2, CCND3, and CCNB2 overexpression indicated accelerated cell cycle progression and evasion of DNA damage checkpoints. Together, this integrative analysis highlights ECM remodeling, cytoskeletal dynamics, and lipid metabolism as major contributors to cisplatin resistance and identifies potential therapeutic markers for TNBC.

Keywords:  Cisplatin resistance; ECM remodeling; Lipidomics; MDA-MB-231; Mass spectrometer; Proteomics; TNBC; Triple-negative breast cancer

DOI:  https://doi.org/10.1021/acs.jproteome.5c01202
FASEB J. 2026 Mar 31. 40(6): e71668

Glucokinase Inactivation Reduces Lysophosphatidylcholine Accumulation to Alleviate High-Fat Diet-Induced Hepatic Steatosis.

Shanshan Chen, Fang Fang, Ke Xu, Ziyue Zhang, Shuhui Ji, Yadi Huang, Na Li, Jingting Qiao, Junhe Wang, Anting Yu, Ming Liu, Yuxin Fan, Yu Fan.

  Partial inactivation of glucokinase (GCK) is typically characterized by mild hyperglycemia and a favorable lipid profile compared to type 2 diabetes. Previous studies have shown that GCK activity influences serum lipid profiles in a diet-dependent manner; however, its role in hepatic lipid metabolism in the context of metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. To address this, we utilized a newly established heterozygous GCK mutation knock-in mouse model (GCKMut) fed either a normal diet (ND) or a high-fat diet (HFD). Under ND conditions, GCKMut mice developed mild hyperglycemia without overt hepatic injury but displayed reduced hepatic glycogen storage, likely due to decreased energy flux. Metabolomic analyses further revealed substantial reprogramming of hepatic amino acid and lipid metabolism in GCKMut mice. Notably, levels of lysophosphatidylcholines (LPCs)-bioactive metabolites implicated in lipotoxicity and the pathogenesis of MASLD-were significantly reduced, as confirmed by ELISA. Under HFD conditions, GCK inactivation markedly attenuated hepatic lipid accumulation, as demonstrated by biochemical quantification and histological analysis. This protective effect was associated with downregulation of genes involved in de novo lipogenesis and fatty acid uptake, as revealed by transcriptomic analyses of primary hepatocytes. Moreover, both the expression of phospholipase A2 (PLA2) and its product LPC were significantly reduced in GCKMut mice, whereas pharmacologic activation of GCK increased hepatic LPC accumulation. These findings suggest that partial GCK inactivation reprograms hepatic metabolism and mitigates lipid-induced hepatic stress, highlighting reduced hepatic GCK activity as a potential therapeutic strategy for early intervention in MASLD.

Keywords:  GCK; GKA; LPC; MASLD; PLA2; T2DM; lipid metabolism; lipotoxicity

DOI:  https://doi.org/10.1096/fj.202503377R
Cancer Biol Med. 2026 Mar 12. pii: j.issn.2095-3941.2025.0444. [Epub ahead of print]

Mitochondrial uncoupling inhibits serine catabolism via FTO activation in metastatic breast cancer.

Xin Jin, Albert M Li, Man Zhao, Haowen Jiang, Yiren Xiao, Michaela Yip, Stavros Melemenidis, Scott Jackson, Yanan Yang, Cathyrin Simmermaker, Meng-Ning Zhou, Subarna Sinha, Daniel J Cuthbertson, Erinn B Rankin, Jiangbin Ye.

   OBJECTIVE: The mitochondrial serine catabolic pathway (MSCP) supports tumor proliferation and metastasis, yet no therapies target the MSCP. Because cancer cells rely on the MSCP when respiration is suppressed, we hypothesized that reactivating respiration would inhibit the MSCP.
METHODS: Mitochondrial respiration was activated in triple negative breast cancer (TNBC) cells using uncouplers [niclosamide ethanolamine (NEN) and BAM15]. Metabolic activity through the MSCP was assessed using U-13C-serine tracing and expression of key MSCP enzymes (SHMT2, MTHFD2, and MTHFD1L) were evaluated at the mRNA and protein levels. The NAD+:NADH ratio and 2-hydroxyglutarate (2-HG) levels were determined using liquid chromatography-mass spectrometry. The role of m6A RNA demethylase fat mass and obesity-associated protein (FTO) in regulating MSCP enzymes was examined using pharmacologic and genetic approaches. The therapeutic potential of mitochondrial uncoupling was tested in vivo using a lung metastasis model.
RESULTS: Activation of mitochondrial respiration with NEN or BAM15 inhibited MSCP activity, as indicated by reduced labeling of glycine and purines from U-13C-serine. Mitochondrial uncoupling markedly decreased the levels of SHMT2, MTHFD2, and MTHFD1L protein, despite unchanged or elevated mRNA levels. This post-transcriptional suppression was mediated by an increased NAD+:NADH ratio, leading to reduced 2-HG production and subsequent activation of FTO. Inhibition of FTO, either pharmacologically or genetically, restored MSCP enzyme protein levels. Dietary mitochondrial uncoupling significantly suppressed lung metastasis in vivo.
CONCLUSIONS: The findings herein demonstrated that mitochondrial uncouplers inhibit MSCP through FTO-dependent m6A demethylation. This work identified mitochondrial uncoupling as a novel and promising therapeutic approach for promoting m6A demethylation and targeting MSCP in metastatic breast cancer.

Keywords:  FTO; Mitochondria uncoupler; breast cancer; m6A; metastasis; one-carbon unit metabolism; serine catabolism

DOI:  https://doi.org/10.20892/j.issn.2095-3941.2025.0444
Cell. 2026 Mar 09. pii: S0092-8674(26)00161-3. [Epub ahead of print]

NAD+ hydrolysis catalyzed by SelO is required for mitochondrial homeostasis.

Xiaofan Jia, Teng Zhang, Chenxi Yang, Kaiyang Liu, Li Wu, Longfei Diao, Yuting Yang, Jie Wu, Yeyi Li, Weiyan Sun, Kai Zhang, Yuhui Jiang, Yuzheng Zhao, Xu Zhang, Peng Jiang, Yideng Jiang, Qiujing Yu, Song Xiang, Yuan Fu, Ting Wang.

  The regulation of nicotinamide adenine dinucleotide (NAD+) is crucial for numerous life processes. However, the mechanisms leading to NAD+ degradation in mitochondria remain insufficiently defined. Through in silico screening of potential NAD-binding proteins, we discovered a mitochondrial reaction in which NAD+ is hydrolyzed to nicotinamide mononucleotide (NMN) and AMP by SELENOO (SelO), using Mn2+ as cofactor. Catalysis depends on SelO's selenocysteine-serine-serine (CSS) C-terminal residues, particularly the selenocysteine 667. In addition to broad metabolic effects, this reaction plays a pronounced role in lipid utilization via SelO directly associating with fatty acid oxidation (FAO) enzymes, and it is conserved in both mammalian cells and bacteria. This reaction is responsive to elevated matrix pH, a signal of enhanced mitochondrial respiration, and protects mitochondria from sustained metabolic overactivation. These findings reveal a conserved mechanism for spatiotemporal NAD+ regulation and highlight its physiological significance in both prokaryotes and eukaryotes.

Keywords:  NAD; fatty acid oxidation; hydrolysis reaction; mitochondrial homeostasis; nicotinamide adenine dinucleotide; selenocysteine

DOI:  https://doi.org/10.1016/j.cell.2026.01.033
Nat Commun. 2026 Mar 14.

Pyruvate metabolism enzyme Dlat induces mitochondria protein hyperacetylation to limit fatty acid oxidation in the HFpEF heart.

Ying Wang, Dong Guo, Jin'ao Zhu, Xue Yang, Chan Wu, Jing Geng, Qi Liang, Nan Sun, Xiaona Niu, Yue Liu, Yanjie Guo, Pan Chang, Yan Li, Lang Hu.

Increased protein acetylation is frequently observed in the failing heart, including in hearts with heart failure with preserved ejection fraction (HFpEF). However, its role in the pathogenesis of HFpEF remains insufficiently investigated. Here, we found that HFpEF hearts displayed significantly protein hyperacetylation, which were predominantly localized to mitochondria and particularly enriched in fatty acid oxidation (FAO) pathway. Notably, Dlat, a pyruvate metabolism enzyme, was identified as the key transacetylase for mitochondrial protein hyperacetylation. Dlat overexpression enhanced FAO-related protein acetylation and exacerbated cardiac lipid metabolism disturbances, whereas Dlat knockdown effectively mitigated FAO inhibition and HFpEF phenotypes. Moreover, we demonstrated that Dlat directly triggers the acetylation of alpha subunit of mitochondrial trifunctional protein (HADHA) at the K728 site, thereby inactivating HADHA enzymatic activity. Our study provides a mechanistic basis linking protein hyperacetylation, FAO inhibition, and HFpEF development. Manipulating mitochondrial protein acetylation may offer potential strategies for therapeutic intervention of HFpEF.

DOI: https://doi.org/10.1038/s41467-026-70703-w
Cells. 2026 Mar 04. pii: 458. [Epub ahead of print]15(5):

Cys340Ser Mutation Abolishing S-Nitrosylation Drives GRK2 Mitochondrial Localization and Dysfunction.

Gizem Kayki Mutlu, Stephanie M Kereliuk, Maya Hoteit, J Kurt Chuprun, Umur Mendes, Yusuf Olgar, Walter J Koch.

  In cardiac pathologies, levels of G protein-coupled receptor kinase 2 (GRK2)-which is involved in receptor desensitization and internalization-are elevated. Beyond these receptor-mediated effects, GRK2 also localizes to mitochondria, where it contributes to pathology. GRK2's activity can be inhibited via S-nitrosylation at Cysteine 340, a post-translational modification mediated by both endogenous and exogenous nitric oxide. Thus, S-nitrosylation is considered as an endogenous brake on GRK2's catalytic activity, counteracting its hyperactivity observed in disease states. However, it remains unclear whether S-nitrosylation also regulates GRK2's influence on mitochondrial function. This study aims to investigate how S-nitrosylation regulates mitochondrial localization and function of GRK2 under hypoxia/reoxygenation stress. To prevent S-nitrosylation at Cys340, we infected AC16 cardiac cells with adenoviruses carrying a GRK2 C340S (Ser) mutation. Our results indicate that inhibiting S-nitrosylation enhances mitochondrial localization of GRK2, especially in response to pathological stimuli. Additionally, mitochondrial function was impaired, as measured by oxygen consumption rates at ATP production. Furthermore, alterations in mitochondrial dynamics and mitophagy led to adverse outcomes when GRK2 was not subject to S-nitrosylation, presumably due to increased catalytic activity. Our findings underscore the importance of GRK2 regulation in cardiac pathologies and suggest that targeting GRK2 or its post-translational modifications may provide therapeutic benefits.

Keywords:  GRK2; S-nitrosylation; hypoxia/reoxygenation; mitochondria

DOI:  https://doi.org/10.3390/cells15050458
Molecules. 2026 Feb 25. pii: 773. [Epub ahead of print]31(5):

Succinylation: A Functional Nexus Between Metabolic Reprogramming and Epigenetic Modifications in Cancer.

Dan Liu, Runtian Li, Mingzhu Li, Fang Xu, Ying Liang, Yang Sun.

  Metabolic reprogramming and epigenetic remodeling are critical features of tumorigenesis. The process of metabolic reprogramming causes metabolites like Succinyl-CoA to accumulate. Succinylation, which depends on succinyl-CoA as the direct donor group, plays a crucial role in regulating cancer metabolism. This involves the transfer of the succinyl group to the lysine residues of substrate proteins resulting in the alteration of the conformation and function of the proteins, modulating several signaling pathways, many of them involved in metabolism. There is growing evidence that succinylation can alter the activity and stability of metabolic enzymes and reshape metabolic networks. Furthermore, it precisely regulates gene expression through the epigenetic modification mechanisms of the histones and non-histone proteins. Lysine succinylation is thus a crucial hub linking tumor metabolic reprogramming and epigenetic remodeling. This review systematically summarizes the dynamic regulatory mechanisms of lysine succinylation and its critical roles in tumor metabolic reprogramming and epigenetic regulation. In the end, we discuss the crosstalk between succinylation and other post-translational modifications (PTMs) as well as recent advances in cancer therapies targeting succinylation.

Keywords:  cancer; epigenetic modification; lysine succinylation; metabolic reprogramming; succinyl-CoA

DOI:  https://doi.org/10.3390/molecules31050773