bims-miptne 2026-04-12 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2026–04–12
fourteen papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

Platelet Cyclophilin D Drives Cholesterol Crystal Embolism-Related Acute Kidney Injury and Kidney Infarction.
Interdependence of cytosolic and mitochondrial calcium dynamics in a hepatocyte cell due to obesity.
Mitochondrial dysfunction in neonatal brain injury: from molecular mechanisms to therapeutic interventions.
Halting Mitochondrial Domino Effect in Acute Liver Injury: Polyphenol-Sr Nanodrugs Attenuate Cell Death and Sterile Inflammation by Combating ROS Burst and Calcium Overload.
Mitochondrial Ubiquitination as a Signaling Hub: Balancing Mitophagy, Inflammation, and Cell Death.
Exosome-Mitochondrial Hybrid Membrane with Targeted Delivery of CO Prevents Mitochondrial Dysfunction and Pyroptosis against Myocardial Ischemia-Reperfusion Injury.
Tumor cell death by ferroptosis contributes to an immunosuppressive tumor microenvironment in syngeneic murine models of cancer.
Mitochondrial Transfer to Endothelial Cells: Mechanisms, Evidence, and Therapeutic Potential.
Mechanisms of human mitochondrial leaderless mRNA translation initiation.
Mitochondria-associated endoplasmic reticulum membranes as aging-sensitive signaling hubs in degenerative musculoskeletal diseases.
A scalable embryonic stem cell-based platform for efficient generation of mitochondrial DNA mutant mice.
From Defence to Dysfunction: The Dual Role of Autophagy and Mitophagy in Cardiomyopathy.
Immunogenic cell death as a promising platform for adjuvant development.
Molecular insights into the binding of curcumin, γ-oryzanol, and sesamin to cyclooxygenase-2 (COX-2): a computational study.

J Am Soc Nephrol. 2026 Apr 10.

Platelet Cyclophilin D Drives Cholesterol Crystal Embolism-Related Acute Kidney Injury and Kidney Infarction.

Cong Li, Luying Yang, John Ku, Peter Boor, Juan Zu, Chao Han, Meisi Kuang, Ye Fei, Fuyao Liu, Hao Long, Qiubo Li, Liang Chang, Huan Yang, Xiang Chu, Heydar Aghakishi, Barbara Mara Klinkhammer, Thomas Gudermann, Elmina Mammadova-Bach, Hans-Joachim Anders.

BACKGROUND: Cholesterol crystal embolism is a severe consequence of advanced atherosclerosis, where intra-arterial cholesterol crystal can trigger organ injury and failure. Cyclophilin D (CypD), a key regulator of the mitochondrial permeability transition pore (MPTP), promotes procoagulant platelet formation and necrosis. We hypothesized that CypD-dependent procoagulant platelet formation enhances cholesterol crystal embolism-induced thromboinflammatory responses and kidney injury.
METHODS: We used CypD-deficient mice and pharmacologic inhibitors (cyclosporine A to block CypD and niflumic acid to inhibit TMEM16F as a downstream effectorof CypD) to determine the role of CypD during cholesterol crystal-induced kidney thromboinflammation and injury.
RESULTS: Cholesterol crystal injection into the renal artery caused infarction, thromboinflammation, and acute kidney injury (AKI) in wild-type mice, whereas CypD-deficient mice were protected. Global or platelet-specific CypD deletion preserved glomerular filtration rate, reduced infarct size, and attenuated tubular damage. Pharmacological inhibition of CypD with cyclosporin A conferred similar protection. Inhibition of TMEM16F-dependent phosphatidylserine (PS) exposure with niflumic acid also reduced CypD-mediated procoagulant activity and limited kidney injury.
CONCLUSIONS: Our findings identified platelet CypD and downstream PS exposure as key mediators of cholesterol crystal-induced thromboinflammation.

DOI: https://doi.org/10.1681/ASN.0000001088
J Biosci. 2026 ;pii: 10. [Epub ahead of print]51

Interdependence of cytosolic and mitochondrial calcium dynamics in a hepatocyte cell due to obesity.

Vedika Mishra, Neeru Adlakha.

The intentional placement of mitochondria in close proximity to calcium ion (Ca2+) release sites enables the quick uptake of cytosolic Ca2+ and the close connection of calcium signaling with energy metabolism. Ca2+ dynamics have been thoroughly investigated in various cells, including hepatocytes. However, little is known about the interaction between cytosolic and mitochondrial Ca2+ dynamics and how it affects adenosine triphosphate (ATP) hydrolysis and nicotinamide adenine dinucleotide (hydrogen) (NADH) production downstream, especially in pathological conditions such as obesity. In this study, we introduce a new reaction-diffusion model of hepatocyte cells that accurately depicts the linked dynamics of mitochondrial and cytosolic Ca2+ in both normal and obese states. Important physiological processes, including intracellular buffering, mitochondrial calcium uniporters, Na+/Ca2+ exchangers, and Ca2+ input sources, are integrated into the model. For precise numerical simulations, a combination of the Crank-Nicolson scheme and a linear finite element approach is used. The results show that obese hepatocytes differ significantly from normal cells in terms of calcium signaling, ATP hydrolysis rates, and NADH production. These findings may help guide future experimental and therapeutic research aimed at metabolic liver illnesses and offer fresh insights into how obesity-induced deregulation of calcium dynamics affects cellular energy metabolism.
J Transl Med. 2026 Apr 10.

Mitochondrial dysfunction in neonatal brain injury: from molecular mechanisms to therapeutic interventions.

Chengqian Teng, Jianjie Wei, Yixiao Zhu, Andi Chen, Xiaohui Chen.

   BACKGROUND: Neonatal brain injury, including hypoxic-ischemic encephalopathy, preterm brain injury, and neonatal infectious brain injury, remains a major cause of death and long-term neurodevelopmental disability worldwide. The immature brain is highly dependent on oxidative metabolism yet particularly vulnerable to energy failure and oxidative stress, placing mitochondria at the core of injury cascades. By integrating disturbances in energy production, redox balance, calcium homeostasis, and cell death signaling, mitochondrial dysfunction is increasingly recognized as a unifying driver of diverse neonatal brain injury phenotypes.
MAIN BODY: This narrative review synthesizes current knowledge on the main clinical forms of neonatal brain injury and their developmental context, alongside an overview of mitochondrial physiology in neural cells, including the regulation of bioenergetics, reactive oxygen species, calcium signaling, mitochondrial dynamics, and inter‑organelle communication. It critically examines how mitochondrial dysfunction contributes to injury across hypoxic-ischemic, preterm, and infectious or inflammatory insults, emphasizing links between impaired oxidative phosphorylation, excessive oxidative and nitrosative stress, calcium overload with pathological opening of the mitochondrial permeability transition pore, activation of apoptosis and regulated necrosis, disrupted mitochondrial fusion-fission balance and biogenesis, and defective mitophagy and mitochondrial quality control. These mitochondrial disturbances precipitate acute neuronal and oligodendroglial injury and hinder the long-term maturation and connectivity of neural circuits. Finally, we review emerging mitochondria‑targeted neuroprotective strategies, focusing on approaches that enhance mitochondrial biogenesis, reduce mitochondrial oxidative stress, and target mitochondrial dynamics to restore mitochondrial homeostasis and improve cellular resilience in the immature brain.
CONCLUSION: By linking specific patterns of mitochondrial dysfunction to distinct forms and stages of neonatal brain injury, this review provides a mechanistic framework for identifying high‑risk infants, refining pathophysiological understanding, and guiding the rational development of mitochondria‑targeted interventions aimed at improving neurological outcomes in vulnerable newborns.

Keywords:  Energy metabolism; Hypoxic–ischemic encephalopathy; Mitochondrial dynamics and mitophagy; Mitochondrial dysfunction; Mitochondria‑targeted therapy; Neonatal brain injury; Neuroprotection; Oxidative stress

DOI:  https://doi.org/10.1186/s12967-026-08104-2
Adv Healthc Mater. 2026 Apr 05. e71121

Halting Mitochondrial Domino Effect in Acute Liver Injury: Polyphenol-Sr Nanodrugs Attenuate Cell Death and Sterile Inflammation by Combating ROS Burst and Calcium Overload.

Min Liu, Shuya Wang, Ruishi Li, Weimin Qi, Tingli Xiong, Xiaojing Shi, Wensheng Chen, Feixiang Ding, Chenglong Wei, Junyan Liu, Niansheng Li, Qiong Huang, Zhaoqian Liu, Kelong Ai.

  Acute liver injury (ALI) is a significant clinical cause of liver failure, potentially occurring at any stage of liver disease and posing a considerable health burden. One prevalent model of ALI stems from acetaminophen (APAP) overdose, where a vicious cycle of "mitochondrial damage-inflammation amplification" and limited availability of small molecular drugs hinder current therapeutic approaches. Herein, a novel tannic acid (TA)-strontium (Sr) nanodrug (SrTA) is proposed. With liver-accumulating and mitochondria-targeting capabilities, SrTA effectively harnesses the broad-spectrum antioxidant properties of TA along with the calcium homeostasis-regulating function of Sr2+. And its therapeutic efficacy surpassed that of an equivalent dose of N-acetylcysteine (NAC). Mechanistically, SrTA directly scavenges mitochondrial reactive oxygen species (ROS), protects mitochondrial integrity, and alleviates endoplasmic reticulum (ER) stress and intracellular oxidative damage. Additionally, SrTA antagonizes calcium signaling, reduces the formation of mitochondria-ER contacts, and inhibits mitochondrial calcium overload. By safeguarding mitochondrial function and preventing the aberrant opening of the mitochondrial permeability transition pore (mPTP), SrTA significantly curtail hepatocyte death and mitigates mtDNA-induced sterile inflammation, effectively halting the injury cascade. In conclusion, this study presents a novel therapeutic strategy for ALI that targets mitochondria and synergistically regulates ROS bursts and calcium overload, achieving multifaceted therapeutic effects.

Keywords:  acute liver injury; calcium overload; inflammation; mitochondria; reactive oxygen species

DOI:  https://doi.org/10.1002/adhm.71121
Biochemistry. 2026 Apr 06.

Mitochondrial Ubiquitination as a Signaling Hub: Balancing Mitophagy, Inflammation, and Cell Death.

Ashwini Kumar, Emmanouil Zacharioudakis.

  Mitochondria are increasingly recognized as signaling organelles that coordinate cell-fate decisions during stress. Because outer mitochondrial membrane (OMM) proteins are exposed to the cytosol, they are prominent substrates for ubiquitination, a dynamic post-translational modification that encodes information through diverse chain architectures and linkage types. In this review, we examine how ubiquitination of OMM proteins functions as a molecular switch that integrates mitochondrial stress signals and engages three major, often antagonistic, stress-response mechanisms: mitophagy, cell death, and innate immune signaling. We highlight an emerging concept that a stress-responsive "ubiquitin code" is written on OMM substrates, in which pathway selection is coordinated by the identity of ubiquitinated OMM proteins together with the linkage type and branching of attached polyubiquitin chains. We provide an updated overview of the E3 ubiquitin ligases and deubiquitinases (DUBs) that write and erase this code and summarize ubiquitin linkage types reported on key OMM substrates across these pathways. For mitophagy, we cover both PARKIN-dependent and PARKIN-independent mechanisms mediated by other E3 ligases and counteracted by DUBs. For innate immunity, we discuss how ubiquitination of OMM proteins regulates the MDA5/RIG-I-MAVS axis and NF-κB signaling. For cell death, we describe how ubiquitination of anti- and pro-apoptotic BCL-2 family proteins can either lower or increase the threshold for the induction of apoptosis. We also highlight the newfound role of PARKIN to drive apoptosis through a BAX/BAK-independent mechanism. Finally, we discuss therapeutic opportunities to reprogram OMM ubiquitination by targeting E3 ligases or DUBs directly, or by using PROTAC- and DUBTAC-based strategies.

Keywords:  E3 ubiquitin ligases; apoptosis; deubiquitinases; innate immune signaling; mitophagy; ubiquitin

DOI:  https://doi.org/10.1021/acs.biochem.6c00007
ACS Nano. 2026 Apr 07.

Exosome-Mitochondrial Hybrid Membrane with Targeted Delivery of CO Prevents Mitochondrial Dysfunction and Pyroptosis against Myocardial Ischemia-Reperfusion Injury.

Lintao Wang, Qianzhi Shi, Chenxiao Jiang, Mengyao Xu, Xinyu Wang, Hao Ren, Xudong Wang, Qijun Fang, Jing Sun, Lina Kang, Xin Chen, Dujuan Sha, Jie Ni.

  Myocardial ischemia-reperfusion (I/R) injury exacerbates cardiac dysfunction and heart failure following clinical revascularization. The main mechanisms involve aberrant accumulation of reactive oxygen species (ROS) that induce mitochondrial dysfunction, trigger pyroptosis, and amplify immune-inflammatory responses. Herein, we developed exosome-mitochondrial hybrid membrane vessels to encapsulate carbon monoxide (EM@CO) for targeted delivery of CO to attenuate myocardial I/R injury. Due to the adhesive properties of exosomes and the homologous mitochondrial targeting capacity of the mitochondrial membrane (MM), EM@CO exhibits sequential targeting from infarcted myocardium to myocardial cell mitochondria. The released CO in mitochondria reduces abnormal mitochondrial ROS generation to maintain mitochondrial function, thereby decreasing mtDNA release and inhibiting pyroptosis in vitro and in vivo. Moreover, a single intravenous injection of EM@CO attenuates inflammatory amplification in cardiac tissue by promoting M1 to M2 macrophage polarization. It can effectively decrease the pro-inflammatory cytokine release and inhibit inflammation, thereby attenuating myocardial infarction and improving cardiac function. In summary, the findings of this study reveal the potential for restoring mitochondrial function through targeted gas therapy to eliminate reactive oxygen species (ROS) and inhibit cellular pyroptosis, which holds promise for ameliorating myocardial ischemia-reperfusion injury.

Keywords:  exosome-mitochondrial hybrid membrane; mitochondrion function; myocardial ischemia-reperfusion injury; pyroptosis; sequential targeted CO gas therapy

DOI:  https://doi.org/10.1021/acsnano.5c21479
Cancer Metab. 2026 Apr 04.

Tumor cell death by ferroptosis contributes to an immunosuppressive tumor microenvironment in syngeneic murine models of cancer.

Nneka E Mbah, Damien Sutton, Hanna S Hong, Rashi Singhal, Rosa E Menjivar, Matthew D Perricone, Heather Giza, Peter Sajjakulnukit, Amy L Myers, Zeribe C Nwosu, Jonathan M Alektiar, Jason Lin, Daniel Long, Anthony C Andren, Li Zhang, Howard C Crawford, Timothy L Frankel, Marina Pasca di Magliano, Luigi Franchi, Yatrik M Shah, Costas A Lyssiotis.

DOI: https://doi.org/10.1186/s40170-026-00428-3
Circ Res. 2026 Apr 10. 138(8): e326982

Mitochondrial Transfer to Endothelial Cells: Mechanisms, Evidence, and Therapeutic Potential.

Gwang-Bum Im, Juan M Melero-Martin.

  Mitochondria are increasingly recognized as central regulators of vascular health, shaping endothelial cell function through roles that extend far beyond energy production. In addition to coordinating redox balance, calcium dynamics, and biosynthetic support, recent studies have revealed that mitochondria participate in intercellular communication, with evidence of transfer events emerging in vascular contexts. Parallel efforts have advanced the deliberate delivery of exogenous mitochondria from preclinical proof-of-principle studies to first-in-human trials, demonstrating that freshly isolated organelles can be harvested and administered in real-time to critically ill patients with favorable early outcomes. The mechanisms underlying these benefits remain incompletely defined, and strategies for efficient and scalable delivery are still emerging. In this review, we prioritize recent evidence linking mitochondrial function to endothelial cell physiology, highlight the nascent but growing field of mitochondrial transfer in the vasculature, and examine how mitochondrial transplantation is evolving from experimental concept to clinical translation. Together, these advances point to new therapeutic avenues for preserving vascular integrity and treating disease.

Keywords:  cell communication; endothelial cells; mitochondria; regenerative medicine; therapeutics

DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326982
Nat Commun. 2026 Apr 04.

Mechanisms of human mitochondrial leaderless mRNA translation initiation.

Shuangjie Shen, Yinghua Xu, Daniel L Kober, Jinfan Wang.

Mitochondrial translation is essential for cellular function, and its dysregulation is associated with mitochondrial disorders and cancer. However, the mechanisms by which human mitochondrial ribosomes initiate translation remain poorly understood, particularly because mitochondrial mRNAs generally lack the 5' untranslated regions that guide translation initiation in bacterial and cytoplasmic systems. Using real-time single-molecule fluorescence measurements, biochemical assays, and cryo-EM analysis, we show that human mitochondrial translation initiation occurs through two parallel pathways. In one pathway, leaderless mRNA first loads onto the 28S small subunit, followed by recruitment of the 39S large subunit to form the 55S initiation complex. In the second pathway, a preassembled 55S monosome directly loads onto leaderless mRNA. Both pathways require recruitment of mtIF2 and fMet-tRNAMet before mRNA binding. However, the monosome-loading pathway tolerates non-formylated Met-tRNAMet and is suppressed by mtIF3. Together, these findings define the heterogeneous pathways of human mitochondrial translation initiation on leaderless mRNAs.

DOI: https://doi.org/10.1038/s41467-026-71535-4
Ageing Res Rev. 2026 Apr 07. pii: S1568-1637(26)00123-6. [Epub ahead of print] 103131

Mitochondria-associated endoplasmic reticulum membranes as aging-sensitive signaling hubs in degenerative musculoskeletal diseases.

Linbo Peng, Kexin Wang, Limin Wu, Lei Yao, Bin Shen, Jian Li.

  Degenerative musculoskeletal diseases (DMDs), including osteoarthritis, osteoporosis, sarcopenia, and intervertebral disc degeneration, are highly prevalent age-related conditions characterized by progressive tissue dysfunction and loss of musculoskeletal integrity. Aging is accompanied by profound alterations in organelle homeostasis, metabolic signaling, and stress adaptation, among which mitochondria-endoplasmic reticulum communication has emerged as a critical regulatory axis. Mitochondria-associated membranes (MAMs) are specialized contact sites that spatially and functionally couple the endoplasmic reticulum and mitochondria, thereby coordinating calcium signaling, redox balance, lipid metabolism, and cell fate decisions. Accumulating evidence indicates that aging-related disruption of MAMs integrity and signaling contributes to mitochondrial dysfunction, oxidative stress, aberrant stress responses, and inflammatory activation across multiple musculoskeletal tissues. In this review, we synthesize current evidence linking MAMs-associated signaling pathways-including calcium flux, reactive oxygen species regulation, unfolded protein response signaling, autophagy, inflammasome activation, and regulated cell death-to the pathogenesis of major degenerative musculoskeletal diseases. We further highlight shared and tissue-specific mechanisms through which age-dependent MAMs dysregulation drives musculoskeletal degeneration. By framing MAMs as aging-sensitive signaling hubs, this review provides an integrated perspective on how organelle crosstalk contributes to degenerative musculoskeletal diseases and identifies conceptual frameworks for understanding disease convergence during musculoskeletal aging.

Keywords:  Calcium homeostasis; Degenerative musculoskeletal diseases; ER–mitochondria crosstalk; Mitochondria-associated ER membranes; Mitochondrial dysfunction

DOI:  https://doi.org/10.1016/j.arr.2026.103131
Proc Natl Acad Sci U S A. 2026 Apr 14. 123(15): e2535453123

A scalable embryonic stem cell-based platform for efficient generation of mitochondrial DNA mutant mice.

Weiwei Fan, Tae Gyu Oh, Lillian Crossley, Hunter Robbins, Mingxiao He, Yang Dai, Morgan L Truitt, Annette R Atkins, Michael Downes, Ronald M Evans.

  Mitochondria are central to energy metabolism and cellular signaling, and mutations in mitochondrial DNA (mtDNA) can disrupt these processes and contribute to human disease. However, progress in defining how mtDNA variation influences adaptation, pathophysiology, and disease susceptibility has been limited by the lack of suitable animal models. Although recent base-editing approaches enable direct mtDNA modification, their low efficiency restricts the generation of diverse models reflecting human mtDNA variation. Here, we develop a scalable embryonic stem (ES) cell-based platform for efficient production of mtDNA mutant mice. Random mutagenesis using an error-prone mtDNA polymerase generates a broad spectrum of mtDNA mutations, which are transferred into ES cells via a multiplexed cybrid fusion strategy coupled with sensitive mutation detection. Optimized ES cell-embryo aggregation enables robust contribution of mtDNA mutant ES cells to host embryos, producing chimeric mice with germline transmission. Using this platform, we generate a library of 155 donor fibroblast lines carrying distinct homoplasmic single-nucleotide mtDNA mutations that produce diverse mitochondrial phenotypes, including impaired oxidative phosphorylation, increased reactive oxygen species, and altered mitochondrial membrane potential. We further generate 34 female C57BL/6 ES cell lines harboring 18 mtDNA mutations across a range of heteroplasmy levels, yielding multiple chimeric mice and achieving germline transmission for one mutation. These data reveal a strong correlation between mitochondrial function and early embryonic development, suggesting a minimal energetic threshold required for normal development. This scalable resource enables systematic investigation of mtDNA variation in physiology, adaptation, disease mechanisms, and therapeutic development.

Keywords:  ES cell; aggregation; mouse model; mtDNA; transgenesis

DOI:  https://doi.org/10.1073/pnas.2535453123
J Biochem Mol Toxicol. 2026 Apr;40(4): e70830

From Defence to Dysfunction: The Dual Role of Autophagy and Mitophagy in Cardiomyopathy.

Nandini Dubey, Gauri Chaturvedi, Pranav Panchbhai, Satnam Singh, Ahsas Goyal, Nirmal Singh, Vishal Kumar Vishwakarma, Neeraj Parakh, Lakshmy Ramakrishnan, Harlokesh Narayan Yadav.

  Cardiomyopathy is a disease unique to the heart muscle that increases a patient's risk of death due to heart failure, contrary to vascular conditions. Cellular powerhouses called mitochondria produce oxygen species that are reactive, that may damage both the mitochondria as well as the heart muscle if they are not managed. They also provide energy for contractions in the heart. Maintaining proper heart function both at base and in reaction to various stress and illness circumstances depends on autophagy as well as mitochondrial autophagy, which eliminates damaged mitochondria. Understanding the pathogenesis of heart diseases, which includes a wide spectrum of cardiovascular problems connected to related cardiomyopathies, is still hampered by autophagy and mitophagy. Additionally, heart failure continues to be a primary source of increased morbidity among people with cardiomyopathy, despite notable advances in lowering death rates from cardiovascular diseases (CVDs). Due to their role in the development of cardiovascular conditions, these cellular processes are appealing targets for diagnosis and therapy. They are crucial for preserving cellular equilibrium and eliminating damaged or malfunctioning components. Further, cardiomyopathies remain a major concern despite the availability of several traditional diagnostic and treatment approaches. Thus, we are going to explore the possible autophagy and mitophagy in the development and progression of cardiomyopathy and provide an overview of current research in this area in this review.

Keywords:  autophagy; cardiomyopathy; heart failure; mitochondria; mitophagy

DOI:  https://doi.org/10.1002/jbt.70830
Curr Opin Virol. 2026 Apr 08. pii: S1879-6257(26)00020-9. [Epub ahead of print]76 101528

Immunogenic cell death as a promising platform for adjuvant development.

Takumi Adachi, Etsushi Kuroda.

Adjuvants play an important role in vaccine efficacy by activating innate immune responses that effectively induce adaptive immunity. Since innate immune cells recognize pathogen-derived factors, such as pathogen-associated molecular patterns (PAMPs), through pattern recognition receptors and trigger inflammatory responses, PAMPs have been extensively exploited as vaccine adjuvants. However, accumulating evidence indicates that factors released from dying or stressed cells, collectively termed damage-associated molecular patterns, also activate innate immune cells and contribute to adjuvant immunogenicity. This review summarizes the molecular mechanisms of major forms of immunogenic cell death (ICD), including immunogenic apoptosis, pyroptosis, and necroptosis, and discusses their relevance to the mode of action of clinically approved and experimental vaccine adjuvants. Collectively, these findings support the concept of ICD as a promising platform for next-generation adjuvant development. A better understanding of cell death-driven immune activation will facilitate the rational design of adjuvants tailored to specific routes of administration, pathogens, and cancer types.

DOI: https://doi.org/10.1016/j.coviro.2026.101528
J Biomol Struct Dyn. 2026 Apr 10. 1-13

Molecular insights into the binding of curcumin, γ-oryzanol, and sesamin to cyclooxygenase-2 (COX-2): a computational study.

Peerayut Dammak, Borvornwat Toviwek, Sittichai Daengprasert, Pissanu Daengprasert, Prapasiri Pongprayoon.

  Cyclooxygenase-2 (COX-2) is a key therapeutic target for inflammatory diseases, cancer, and osteoarthritis (OA). Thus, several COX-2 inhibitors have been developed. However, their clinical use has been limited due to the cardiovascular, hepatic, and renal adverse effects. Given these limitations, the safer and more nuanced COX-2 inhibitors are needed. Curcumin (CU) from Curcuma longa, γ-oryzanol (GO) from rice bran oil, and sesamin (SM) (from sesame seed) were experimentally found to show the COX-2 inhibitory effect where a molecular detail is limited. Therefore, in this study, we investigated the binding mechanisms of CU, GO, and SM to COX-2 using Molecular Dynamics (MD) simulations. Our results show that all three ligands bind stably to COX-2 and adopt an I-shaped conformation spanning both the central binding site and proximal binding site. One end of each ligand, containing aromatic moiety, interacts with aromatic residues adjacent to heme group (Y385 for GO and W387 for CU and SM), while the remaining structure extends toward the proximal site. Hydrophobic interactions are the primary contributors to ligand binding, with CU and GO exhibiting stronger binding affinities than SM. Further experiments are needed. Collectively, these findings provide molecular-level insights that can support the rational development of plant-derived compounds as complementary or alternative therapeutics targeting inflammatory and pain-related disorders.

Keywords:  COX-2; MD simulations; curcumin; oryzanol; sesamin

DOI:  https://doi.org/10.1080/07391102.2026.2655804