bims-matara 2026-08-30 papers

bims-matara

Biomed News

on MTOR

Issue of 2026–08–30
fourteen papers selected by
Lucas van Endert, Institut du Cerveau

Ultra-Processed Diets and Pediatric Acne: Insulin-mTOR Activation and Its Potential Role in Cutaneous Inflammation.
Reprogramming immunometabolism: linking nutrient sensing, cell death, and therapeutic innovation.
The TORC-SnRK Axis: An Integrative Signaling Framework Balancing Growth and Stress Responses in Plants.
MITF Activation Is a Feature of Clear Cell and Conventional Fibrous Papule.
Impaired Chaperone-Mediated Autophagy Accelerates Intervertebral Disc Degeneration by Inducing MIDN Accumulation to Target TSC2 for Proteasomal Degradation.
miR-486-5p suppresses autophagy in hepatocellular carcinoma via activation of the AKT/mTOR signalling pathway.
Amino Acid Metabolism in Health and Disease.
Disruption of hippocampal upstream regulators of mTOR and insulin pathways in Down syndrome with Alzheimer's disease neuropathology: Preliminary observations.
Black Sheep: Pseudokinases Bucking the Trend to Reveal Non-Catalytic Kinase Functions.
Mathematical Modeling of Dietary Timing- and Protein Quality-Responsive Liver Circadian Clock and its Function on Ribosome Biogenesis.
Pharmacological mTOR pathway activation does not enhance trophectoderm differentiation in bovine embryos.
Vitamin D and Metabolic Syndrome: Molecular Mechanisms and Clinical Implications: A Narrative Review.
Beyond Kinase Inhibition: From Catalytic Blockade to Control of Protein Fate.
Autophagy-Targeted Vascular Remodeling in Pulmonary Arterial Hypertension: Molecular Mechanisms and Therapeutic Perspectives.

Int J Mol Sci. 2026 Aug 08. pii: 7123. [Epub ahead of print]27(16):

Ultra-Processed Diets and Pediatric Acne: Insulin-mTOR Activation and Its Potential Role in Cutaneous Inflammation.

Yasmeen Magharehabed, Zainab Ibrahim, Hesham Shiekhtholth, Nabiha Yusuf.

  Acne vulgaris is an inflammatory cutaneous condition that disproportionately affects the pediatric population. While there are several risk factors, emerging evidence suggests that ultra-processed foods (UPFs), as part of Western dietary patterns, may contribute to acne pathophysiology through activation of inflammatory pathways, such as mTORC1. This comprehensive review synthesizes current evidence regarding acne pathogenesis in conjunction with diet-associated inflammatory cascades to better illustrate the potential role of diet as an adjunct to clinical management in pediatric patients. The current literature suggests that increased insulin/IGF-1 levels may contribute to alterations in the skin and gut microbiota. Additionally, components commonly found in UPFs have been proposed to activate the mechanistic target of rapamycin complex (mTORC1) through insulin/IGF-1-dependent and -independent mechanisms, perpetuating inflammatory pathways that give rise to acne pathogenesis. However, the majority of available evidence is derived from adult cohorts; pediatric-specific evidence remains limited. While studies have demonstrated clinical significance in acne severity with dietary interventions, future high-quality studies are required. Through understanding the relationship between diet and acne pathogenesis, future therapeutic and preventative strategies may be developed to improve pediatric acne clinical outcomes.

Keywords:  IGF-1; acne vulgaris; mTORC1; pediatric dermatology; skin microbiome; ultra-processed foods

DOI:  https://doi.org/10.3390/ijms27167123
Immunol Res. 2026 Aug 25. pii: 94. [Epub ahead of print]74(1):

Reprogramming immunometabolism: linking nutrient sensing, cell death, and therapeutic innovation.

Priya Sharma.

  Development of Immunometabolism as a central paradigm in the modern immunology has revolutionized the understanding of metabolism from being a passive supplier of energy to an important determinant of immune cell fate and function. Immune cells are activated, differentiated, survive and undergo programmed cell death through the activity of distinct metabolic programs, including those involving glycolysis, oxidative phosphorylation (OXPHOS), nutrient sensing through Mechanistic Target of Rapamycin (mTOR), AMP-Activated Protein Kinase (AMPK), and HIF‑1α. Rapid proliferation and production of cytokines by effector T cells and pro-inflammatory macrophages is mediated by glycolysis, while persistence and tolerance by memory T cells and reparative macrophages is mediated by oxidative metabolism. Metabolic input and output are also coupled with immune specialization and cell death mechanisms, such as apoptosis, Pyroptosis and ferroptosis, via mitochondrial bioenergetics and production of Reactive Oxygen Species (ROS). Altered immunometabolism is linked to a variety of pathologies: competition for nutrients in tumor physiology leads to T cell exhaustion; an unchecked glycolytic pathway maintains a state of autoimmune inflammation; pathogens exploit host metabolism to escape immunological control; and metabolic diseases, such as obesity and diabetes, foster chronic low‑grade inflammation. Therapies such as rapamycin, metformin, glycolysis and glutamine inhibitors, and metabolic adjuvants in vaccines underscore the translational potential of targeting metabolic checkpoints. But there are still debates on the specificity of the metabolic intervention, the balance between the effector and regulation responses, and the restrictions of the existing experimental models. New strategies, such as single-cell metabolomics and precision medicine, are expected to bring in more sophisticated ways for fine-tuning immune metabolism. Immunometabolism is thus a paradigm shift, with metabolism now being at the heart of immune regulation, and providing new opportunities for critical evaluation and translational innovation in cancer, autoimmunity, infections and metabolic disease.

Keywords:  Cancer immunotherapy; Glycolysis; Immune cell death; Immunometabolism; Metabolic reprogramming; Nutrient sensing

DOI:  https://doi.org/10.1007/s12026-026-09831-w
Mol Plant. 2026 Aug 22. pii: S1674-2052(26)00276-5. [Epub ahead of print]

The TORC-SnRK Axis: An Integrative Signaling Framework Balancing Growth and Stress Responses in Plants.

Gao-Jia Yan, Qiu-Yan Yang, Yu-Song Liu, Jian Li, Hui Xue, Sheng Luan, Kun-Lun Li.

  As sessile organisms, plants must continuously balance growth and stress adaptation in response to fluctuating environments. This balance is largely governed by two evolutionarily conserved kinase systems, the Target of Rapamycin Complex (TORC) and Snf1-Related Kinases (SnRKs). Under favorable conditions, plants adopt a "growth mode" in which sufficient nutrients, energy, and growth-promoting hormones activate TORC to drive anabolic metabolism, cell proliferation, and biomass accumulation. By contrast, under adverse conditions such as energy limitation, nutrient deprivation, and other environmental stresses, plants shift to an "adaptation mode" in which stress-associated cues, including low ATP, stress hormones (e.g., ABA), and Ca2+ transients activate distinct SnRK modules (SnRK1, SnRK2, and SnRK3/CIPKs) to promote catabolic reprogramming and enhance stress tolerance. Recent advances support a unifying model in which TORC and SnRKs reciprocally regulate each other, enabling plants to switch between growth and adaptation. In this review, we summarize how diverse growth-associated signals converge on TORC and how stress-specific signaling inputs selectively activate SnRK modules, and we highlight recent progress in elucidating the molecular mechanisms underlying TORC-SnRK crosstalk. We propose that the TORC-SnRK axis serves as a central signaling module that integrates energy, hormonal, and Ca2+ signals to coordinate growth and stress responses. This conceptual framework facilitates a mechanistic understanding on how plants optimize fitness in fluctuating environments and offers potential strategies for improving crop performance through targeted manipulation of this regulatory network.

Keywords:  Growth-stress balance; Nutrient and energy sensing; SnRK; Stress signaling; TOR complex

DOI:  https://doi.org/10.1016/j.molp.2026.08.018
J Cutan Pathol. 2026 Aug 28.

MITF Activation Is a Feature of Clear Cell and Conventional Fibrous Papule.

David J Papke, Daniel Pissaloux, Igor Odintsov, Esther Baranov, Jason L Hornick, Arnaud de la Fouchardiere, John Hanna.

  Fibrous papule, also known as angiofibroma, is a common benign cutaneous lesion with a predilection for the nose and, to a lesser extent, other parts of the face. Most cases occur sporadically, although similar lesions occur in tuberous sclerosis where they are sometimes referred to as adenoma sebaceum. In addition to conventional fibrous papule, several morphologic subtypes have been described which are much less common and may be more challenging to recognize. Clear cell fibrous papule is distinguished by its voluminous clear cytoplasm and the expression of NKI-C3, a marker of lysosomes. Here we show that clear cell fibrous papule is characterized by MITF overexpression and activation, and is accompanied by overexpression of GPNMB, a direct transcriptional target of MITF. Surprisingly, MITF overexpression was also seen in both conventional fibrous papule and tuberous-sclerosis-associated fibrous papules, suggesting a potentially unifying cellular feature in all three subtypes of fibrous papule. Furthermore, since the mTOR pathway, which is dysregulated in tuberous sclerosis, regulates the MITF/TFE family of transcription factors, these findings also suggest a potential mechanistic link between sporadic and syndromic fibrous papules.

Keywords:  MITF; angiofibroma; clear cell; fibrous papule; lysosome; melanosome

DOI:  https://doi.org/10.1111/cup.70203
Adv Sci (Weinh). 2026 Aug 27. e77428

Impaired Chaperone-Mediated Autophagy Accelerates Intervertebral Disc Degeneration by Inducing MIDN Accumulation to Target TSC2 for Proteasomal Degradation.

Xianglong Chen, Haiyang Gao, Wang Wu, Pengzhi Shi, Yuhang Chen, Anran Zhang, Zhangrong Cheng, Wenbo Wu, Zimu Yu, Yukun Zhang.

  Intervertebral disc degeneration (IDD) is a leading cause of low back pain with incompletely understood mechanisms. Although autophagy dysfunction is a documented contributor to IDD, the precise pathobiological role of chaperone-mediated autophagy (CMA) remains poorly understood. Here, we demonstrate that CMA activity is downregulated in nucleus pulposus cells (NPCs) from IDD patients and IL-1β-induced rat intervertebral disc cell models, causing cytoplasmic accumulation of a novel CMA substrate, Midnolin (MIDN). Accumulated MIDN bypasses the ubiquitin-proteasome system and directly binds to Tuberous Sclerosis Complex 2 (TSC2), mediating its degradation. TSC2 loss relieves mechanistic target of rapamycin complex 1 (mTORC1) inhibition, resulting in mTORC1 hyperactivation, which drives cellular senescence, senescence-associated secretory phenotype (SASP), and extracellular matrix (ECM) degradation in NPCs. In vitro and in a rat caudal needle puncture model, MIDN knockdown (shRNA), CMA activation (LAMP2A overexpression), or mTORC1 inhibition (Rapamycin) significantly attenuated IL-1β or MIDN overexpression-induced senescence and disc degeneration. Our findings reveal an "Impaired CMA-MIDN accumulation-TSC2 degradation-mTORC1 activation" axis central to IDD pathogenesis, offering potential therapeutic targets.

Keywords:  autophagy; cellular senescence; intervertebral disc degeneration; low back pain; proteostasis

DOI:  https://doi.org/10.1002/advs.77428
Mol Biomed. 2026 Aug 24. pii: 148. [Epub ahead of print]7(1):

miR-486-5p suppresses autophagy in hepatocellular carcinoma via activation of the AKT/mTOR signalling pathway.

Yazheng Li, Mei Hou, Yong Jin, Xiangjin Zhuang, Yueyi Li, Wen Yang, Hongyang Wang, Qiyu Feng.

  Autophagy is controlled by a complex signalling network and is closely linked to the initiation and progression of hepatocellular carcinoma (HCC). However, how microRNAs (miRNAs) regulate autophagy in HCC remains incompletely understood. In this study, we identified microRNA-486-5p (miR-486-5p) as a tumour-associated microRNA that is enriched in circulating exosomes derived from patients with HCC. Elevated miR-486-5p promoted proliferation and suppressed apoptosis in HCC cell lines under stress conditions. Mechanistically, miR-486-5p directly targets the 3' untranslated region of the phosphatase and tensin homologue (PTEN) gene, thereby decreasing the production of the PTEN protein and consequently leading to the activation of the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signalling pathway. This phenomenon was accompanied by the inhibitory phosphorylation of unc-51 like autophagy-activating kinase 1 (ULK1), which resulted in impaired autophagy. The pharmacological inhibition of AKT or mTOR led to the restoration of autophagy and the attenuation of miR-486-5p-driven growth and survival advantages. Furthermore, the transcription factor MYB was found to bind the promoter of ankyrin-1 (ANK1), the host gene of miR-486-5p, and to drive its expression. In an orthotopic liver tumour model, the liver-targeted delivery of miR-486-5p accelerated tumour expansion, an effect that was reversed by AKT or mTOR blockade. Collectively, these findings delineate a MYB/miR-486-5p/PTEN/AKT/mTOR signalling axis that constrains autophagy to facilitate HCC progression, suggesting potential avenues for biomarker development and therapeutic intervention.

Keywords:  Autophagy; Hepatocellular carcinoma; MYB; MiR-486-5p; PTEN

DOI:  https://doi.org/10.1186/s43556-026-00556-8
MedComm (2020). 2026 Sep;7(9): e70930

Amino Acid Metabolism in Health and Disease.

Zhiwei Su, Jinyu Liu, Xiaoliang Deng, Yanqun Luo, Haiping Xue, Lei Wang, Lianjun Xing, Tao Wu.

  Metabolic reprogramming is a central feature of many human diseases, and therapies that target altered metabolic dependencies are moving from concept to clinical testing. Amino acid homeostasis links essential and nonessential amino acid supply with branched-chain amino acid (BCAA) catabolism, one-carbon metabolism, mechanistic target of rapamycin complex 1 (mTORC1)/general control nonderepressible 2 (GCN2) nutrient sensing, glutathione-dependent redox control, epigenetic regulation, and the gut microbiota-amino acid axis. When this network is disturbed, amino acid flux can contribute to disease initiation and progression rather than simply mirroring established pathology. This review synthesizes how amino acid metabolism supports the nervous, cardiovascular, digestive, metabolic-endocrine, immune, skeletal, urinary and reproductive systems, as well as malignant and inherited metabolic disorders. We also examine how pathway-level disturbances converge on excitotoxicity, endothelial dysfunction, insulin resistance, inflammation, fibrosis, immune escape, toxic metabolite accumulation, and impaired fertility. Rather than catalog isolated findings, we emphasize unifying principles and unresolved controversies, including the context-dependent effects of BCAA signaling, the causal versus biomarker status of circulating amino acid signatures, host-gut microbiome crosstalk, and the therapeutic window of dietary, enzymatic, transporter-targeted, and microbiota-based interventions. Finally, we assess clinical translation, drawing lessons from late-stage trial failures and emerging strategies with realistic potential for precision metabolic therapy.

Keywords:  amino acid metabolism; branched‐chain amino acids; clinical translation; epigenetic regulation; gut microbiota–amino acid axis; metabolic reprogramming; one‐carbon metabolism; redox homeostasis

DOI:  https://doi.org/10.1002/mco2.70930
Alzheimers Dement. 2026 Aug;22(8): e71776

Disruption of hippocampal upstream regulators of mTOR and insulin pathways in Down syndrome with Alzheimer's disease neuropathology: Preliminary observations.

Abigail J Nordbeck, Mitchell Martá-Ariza, Henric Ek Olofsson, Evgeny Kanshin, Beatrix Ueberheide, Ken Jones, Bridget Sanford, Eric D Hamlett, Elizabeth Head, Elliott J Mufson, Sylvia E Perez, Thomas Wisniewski, Samuel Guzman, Ann-Charlotte Granholm.

   INTRODUCTION: Down syndrome (DS) is caused by a complete or partial trisomy of chromosome 21, resulting in variable intellectual disabilities and a high risk for early-onset Alzheimer's disease (DS-AD). Dysregulation of the mammalian target of rapamycin (mTOR) and insulin (INS) signaling pathways has been reported in DS. We hypothesized that upstream alterations in these two pathways contribute to hippocampal dysfunction in DS-AD.
METHODS: We used spatial transcriptomics and localized proteomic techniques to examine mTOR/INS signaling pathways in subregions of the hippocampus in post mortem tissue from individuals with DS-AD and age-matched neurotypical controls.
RESULTS: mTOR pathways were significantly altered in specific hippocampal subfields in DS-AD, and INS pathways were significantly altered in dentate granule neurons.
DISCUSSION: These preliminary spatial transcriptomics and localized proteomics findings demonstrate an interplay between select hippocampal mTOR/INS pathways and cellular populations, suggesting potential novel drug targets and early biomarkers for DS.

Keywords:  Alzheimer's disease; Down syndrome; insulin; localized proteomics; mammalian target of rapamycin; pathway analysis; spatial transcriptomics; upstream regulators

DOI:  https://doi.org/10.1002/alz.71776
IUBMB Life. 2026 Aug;78(8): e70125

Black Sheep: Pseudokinases Bucking the Trend to Reveal Non-Catalytic Kinase Functions.

James M Murphy, Natalia Jura, Peter D Mace.

  Pseudokinases are the catalytically-dead counterparts of protein kinases and, over the past 20 years, have increasingly garnered attention as crucial signaling entities-comprehensively dispelling the possibility that they are merely evolutionary remnants or cellular passengers. The field has been framed by a sequence-based definition of a pseudokinase, where the absence of one or more of the three critical catalytic residues required for phosphoryl transfer in conventional protein kinases has allowed their classification. As a result, pseudokinases have been defined by their dissimilarity to active kinases, meaning they are the outcasts or black sheep of the kinome. Pseudokinases are prevalent in nature, accounting for 10% or more of the kinase complement throughout phyla, and have been reported to mediate diverse functions in controlling the activities of other enzymes allosterically, mediating signaling complex assembly, serving as conformational switches and as negative regulators of signaling flux. Here, we review our current understanding of the varied pseudokinase functions as a window toward understanding non-catalytic functions of conventional protein kinases, the challenges associated with defining pseudokinases-especially in cases where cryptic catalytic activities have been reported-and the emergence of pseudokinases as pharmacological targets.

Keywords:  catalytically‐dead; protein interactions; pseudoenzyme; signal transduction

DOI:  https://doi.org/10.1002/iub.70125
Physiol Genomics. 2026 Aug 26.

Mathematical Modeling of Dietary Timing- and Protein Quality-Responsive Liver Circadian Clock and its Function on Ribosome Biogenesis.

Lingjun Lu, Jordan L Levy, Tracy G Anthony, Ioannis P Androulakis.

  Independent of the suprachiasmatic nucleus, peripheral clocks can be strongly entrained by dietary signals. Although feeding time has been widely studied, the effects of food quality-particularly nutrient availability and stress-on peripheral circadian entrainment and metabolic regulation remain less understood. We developed a semi-mechanistic mathematical model of peripheral clock synchronization and clock-controlled ribosome biogenesis (RiBi) in response to feeding/fasting cycles and rhythms in dietary essential amino acid (EAA) availability. The model integrates EAA-sensitive signaling through mammalian target of rapamycin complex 1 (mTORC1) and the general control nonderepressible 2 (GCN2)-mediated integrated stress response (ISR), together with ribosomal protein expression as a metabolic endpoint. We used the model to examine circadian entrainment under nutrient stress, adaptation during transitions between feeding schedules with EAA insufficiency, and stress-related mechanisms that may restore circadian and metabolic function. Simulations showed that mTORC1 and GCN2-ISR signaling jointly regulate metabolic entrainability and stress adaptation and are required to maintain circadian synchronization and RiBi dynamics during nutrient stress. The model also predicted that differences in homeostatic adaptation can produce individualized recovery trajectories after transient dietary disruption. Finally, appropriate modulation of GCN2-ISR signaling mitigated disruption-associated RiBi hyperactivation by leveraging dietary EAA rhythms to restore clock function. These findings identify dietary EAA stress and its regulatory pathways as important determinants of peripheral circadian entrainment and metabolic adaptation, supporting the development of personalized nutrition-based strategies for circadian disruption-related chronic disease.

Keywords:  Dietary timing; Essential amino acids; circadian entrainement; modeling; nutrient sensing

DOI:  https://doi.org/10.1152/physiolgenomics.00152.2026
Reprod Biol. 2026 Aug 25. pii: S1642-431X(26)00106-3. [Epub ahead of print]26(4): 101284

Pharmacological mTOR pathway activation does not enhance trophectoderm differentiation in bovine embryos.

Mirela Soares Vilioti, Beatriz Cartaxo Ragnelli, Francieli Perroni Berling, Camilla Mota Mendes, Mayra Elena Ortiz D'Ávila Assumpção, Marcelo Demarchi Goissis.

  The formation of the blastocyst is a highly orchestrated process involving different cellular and molecular aspects. In mice, the mTOR pathway influences the Hippo pathway, leading to expression of trophectoderm (TE)-related genes. However, these mechanisms are not fully characterized in bovine embryos, and biological pathways are not always conserved across species. We hypothesized that mTOR pathway positively influences the TE differentiation in bovine embryos. This study aimed to evaluate the effects of the mTOR agonist MHY1485 (MHY) on TE formation in in vitro-produced bovine embryos. Embryos were treated at 96 h post insemination (hpi) with 2 µM MHY or DMSO (vehicle) until 144 hpi or 192hpi. At 144 hpi, morulae were collected for gene expression analysis of CDX2, GATA3, OCT4, SOX2, TFAP2C and YAP1. No significant differences in mRNA expression were observed between the Control, DMSO or MHY groups. At 192 hpi, embryos were fixed for confocal microscopy to assess the TE marker GATA3 and the Hippo-related transcription factor YAP1. While total cell and inner cell mass counts remained unaffected, TE cell numbers were significantly reduced in the DMSO group compared to both the Control and MHY groups. Furthermore, nuclear YAP1 intensity was lower in the DMSO group compared to the MHY group, in which YAP1 was lower than the Control. In conclusion, pharmacological activation of the mTOR pathway did not positively influence TE differentiation in bovine embryos; however, it effectively rescued the unexpected negative effects induced by the vehicle (DMSO) on TE cell number and YAP1 signaling.

Keywords:  Blastocyst; DMSO; Hippo pathway; Inner cell mass

DOI:  https://doi.org/10.1016/j.repbio.2026.101284
Int J Mol Sci. 2026 Aug 07. pii: 7101. [Epub ahead of print]27(16):

Vitamin D and Metabolic Syndrome: Molecular Mechanisms and Clinical Implications: A Narrative Review.

Héctor Fuentes-Barría, Raúl Aguilera-Eguía, Miguel Alarcón-Rivera, Cherie Flores-Fernández.

  Metabolic syndrome (MetS) is a complex multisystem disorder characterized by insulin resistance, central obesity, dyslipidemia, hypertension, and chronic low-grade inflammation, all of which substantially increase the risk of type 2 diabetes mellitus and cardiovascular disease. The aim of this narrative review is to examine the role of vitamin D in the pathophysiology of MetS from a multisystem perspective. Specifically, it synthesizes current evidence on the molecular mechanisms through which vitamin D may influence inter-organ communication, insulin resistance, adipose tissue dysfunction, hepatic metabolism, skeletal muscle function, chronic inflammation, oxidative stress, and mitochondrial homeostasis, highlighting its potential contribution to the prevention and management of MetS. Current evidence indicates that MetS should not be regarded merely as a cluster of isolated metabolic abnormalities but rather as a disorder characterized by disrupted molecular signaling and impaired communication among metabolically active organs. In this context, experimental and preclinical evidence suggests that vitamin D, through activation of the vitamin D receptor (VDR), modulates key signaling pathways, including AMP-activated protein kinase (AMPK), the mechanistic target of rapamycin (mTOR), nuclear factor kappa B (NF-κB), and peroxisome proliferator-activated receptor gamma (PPAR-γ), thereby influencing insulin sensitivity, inflammation, oxidative stress, mitochondrial function, and metabolic homeostasis. Nevertheless, clinical evidence remains heterogeneous due, in part, to the lack of consensus regarding serum 25-hydroxyvitamin D thresholds for defining vitamin D status, as well as differences in baseline vitamin D concentrations, supplementation regimens, study populations, and methodological designs. Overall, the available evidence suggests that vitamin D should be considered an adjunct to lifestyle-based interventions rather than a stand-alone therapeutic strategy. Future research is warranted to clarify its clinical utility in the prevention and management of MetS.

Keywords:  metabolic syndrome; molecular biology; treatment outcome; vitamin D

DOI:  https://doi.org/10.3390/ijms27167101
Chimia (Aarau). 2026 Aug 19. 80(7-8): 501-508

Beyond Kinase Inhibition: From Catalytic Blockade to Control of Protein Fate.

Johan Diepeveen, Zuzanna Kozicka.

  Kinase inhibitors are a cornerstone of modern drug discovery, with more than 100 approved compounds which have had a transformative impact in precision oncology and inflammatory disease. Their success has rested largely on small-molecule control of catalytic activity through ATP-site engagement; a framework that leaves important biology unaddressed, including non-catalytic kinase functions, resistance driven by active-site mutation, and the limits of selectivity imposed by pocket conservation. Against this backdrop, the observation that kinase inhibitors can reduce target protein abundance has gained new mechanistic depth. Chaperone deprivation, supercharging of native degradation circuits, and context-dependent mutant-selective depletion mark distinct routes through which inhibitor binding can intersect with cellular proteostasis. The kinase inhibitor CR8 extends this logic into chemically encoded degradation: CR8 acts as a molecular glue degrader by creating, within the ligand-bound kinase complex, a composite surface that directly recruits a ubiquitin ligase, resulting in cyclin K degradation. Thalidomide analogues can degrade kinases through scaffolds that do not bind the kinase in isolation: ligase-binding compounds that recruit neosubstrate kinases through recognition of structural surface degrons. Deliberately engineered PROTACs encode ligase-target proximity through heterobifunctional architecture to convert kinase binders into degraders. Beyond degradation, induced-proximity mechanisms - from the clinically established rapamycin to bifunctional molecules that redirect kinase activity or restrict inhibition to tumour cells - show how small molecules can reshape kinase interaction states rather than simply block active sites. Together, these examples define an expanding pharmacological vocabulary for kinase drug discovery: one that asks not only whether a molecule inhibits its target kinase, but how ligand binding rewires protein stability, interactions, localisation, and function.

Keywords:  Kinase inhibitors; Molecular glues; PROTACs; Targeted protein degradation

DOI:  https://doi.org/10.2533/chimia.2026.501
J Cardiovasc Dev Dis. 2026 Aug 13. pii: 387. [Epub ahead of print]13(8):

Autophagy-Targeted Vascular Remodeling in Pulmonary Arterial Hypertension: Molecular Mechanisms and Therapeutic Perspectives.

Miao Li, Limei Piao.

  Pulmonary arterial hypertension (PAH) is a severe cardiovascular disease characterized by progressively increased pulmonary vascular resistance and right heart failure. Its pathogenesis involves multiple factors, including genetic predisposition, inflammation, oxidative stress, and imbalances between cell proliferation and apoptosis. Recent studies indicate that autophagy has a context-dependent dual role in PAH. Flux-competent autophagy may be protective by clearing damaged mitochondria, limiting excessive inflammation, and maintaining metabolic homeostasis, whereas excessive autophagy initiation or impaired autophagosome-lysosome degradation may promote metabolic dysfunction, inflammatory signaling, abnormal vascular cell phenotypes, and pulmonary vascular remodeling. This focused narrative review summarizes the molecular mechanisms and key signaling pathways linking autophagy to PAH, with emphasis on PTEN-induced kinase 1 (PINK1)/Parkin-mediated mitophagy and the AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) energy-sensing axis. It also evaluates potential therapeutic strategies targeting key nodes of autophagy, such as AMPK activators and mTOR inhibitors, along with their clinical research progress. Finally, this review provides an outlook on future research directions, emphasizing the need to further elucidate the dynamic regulatory mechanisms and cell-type specificity of autophagy in order to advance the clinical translation of autophagy-targeted precision therapies for PAH.

Keywords:  AMPK/mTOR; PAH; autophagy; mitophagy; pulmonary arterial hypertension; therapeutic targets; vascular remodeling

DOI:  https://doi.org/10.3390/jcdd13080387