MedComm - Future medicine最新文献

{"title":"Mitochondrial Proteotoxicity: A New Frontier in Type 2 Diabetes?","authors":"Junlin Wei, Fang Wang","doi":"10.1002/mef2.70054","DOIUrl":"10.1002/mef2.70054","url":null,"abstract":"<p>In a recent study published in <i>Nature Metabolism</i>, Li et al. [<span>1</span>] identified mitochondrial proteotoxicity due to impaired protein folding as a key driver of β-cell failure in type 2 diabetes (T2D), shifting the focus from canonical endoplasmic reticulum (ER) stress paradigms. The chaperone function of the LONP1–mitochondrial heat shock protein 70 (mtHSP70) axis was found to be essential for maintaining mitochondrial proteostasis, offering a novel therapeutic target for preserving β-cell function in diabetic patients.</p><p>The global prevalence of T2D is projected to exceed 1.3 billion by 2050, underscoring the urgent need to identify novel mechanisms of β-cell failure and druggable targets. Large-scale genome-wide association study (GWAS) and multi-omics technologies have advanced our understanding of T2D's genetic heterogeneity. A trans-ancestry meta-analysis of over 2.5 million individuals identified eight mechanistic clusters, each with distinct clinical manifestations and complication risks, highlighting the necessity for targeted therapies to enable precise treatment.</p><p>While ER stress has long been implicated in β-cell dysfunction, Li et al. provide compelling evidence that mitochondrial proteotoxicity represents an earlier and more prominent event in human T2D islets. Using unbiased proteomics, they found significant enrichment of insoluble mitochondrial protein aggregates in islets from T2D donors, a signature distinct from ER protein misfolding. The mitochondrial protease LONP1 was identified as a crucial guardian against this proteotoxicity, with its expression notably reduced in T2D β-cells. Using β-cell-specific <i>Lonp1</i> knockout mice, the authors demonstrated that LONP1 deficiency recapitulates key features of human T2D islets observed in their proteomic analysis, including accumulation of misfolded mitochondrial proteins, bioenergetic deficits, oxidative stress, and β-cell apoptosis. Direct causal evidence in human islets, however, remains to be established. Most importantly, LONP1 protects β-cells via a protease-independent, chaperone-like function by forming a complex with mitochondrial HSP70. The structural basis involves LONP1's chaperone domain interacting with mtHSP70's substrate-binding domain, though the regulation of this complex under diabetic stress requires further investigation. Furthermore, the study linked inadequate adaptive response in T2D to downregulation of ATF5, a known regulator of the mitochondrial unfolded protein response and direct transcriptional activator of <i>LONP1</i> (Figure 1).</p><p>However, to fully appreciate the implications of Li et al.'s findings on LONP1, they must be contextualized within the highly integrated mitochondrial quality control (MQC) network. Mitochondria maintain proteostasis through a coordinated system involving compartment-specific proteases, chaperones, and organellar dynamics. Furthermore, the inner membrane protein TMBIM5 directly binds and inh","PeriodicalId":74135,"journal":{"name":"MedComm - Future medicine","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mef2.70054","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147585248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The DYRK Family: A Key Regulator of Metabolic Homeostasis and Its Therapeutic Potential in Kidney Diseases","authors":"Yixuan Zhu,&nbsp;Pengfei Qiao,&nbsp;Yukun Gan,&nbsp;Xiushuo Fu,&nbsp;Xiayue Huang,&nbsp;Sirui Sun,&nbsp;Yafei Gou,&nbsp;Wenjie Xia,&nbsp;Feng Ma,&nbsp;Limin Liu","doi":"10.1002/mef2.70050","DOIUrl":"https://doi.org/10.1002/mef2.70050","url":null,"abstract":"<p>The dual-specificity tyrosine-regulated kinase (DYRK) family, a conserved serine/threonine kinase group, plays a pivotal role in the regulation of metabolic homeostasis by modulating glucose/lipid metabolism, oxidative stress, and calcium-phosphorus balance. Mammalian DYRKs are classified into Class I (DYRK1A and DYRK1B) and Class II (DYRK2, DYRK3, and DYRK4) based on their structural differences, tissue-specific expression, and functional diversity in maintaining systemic metabolic balance. Dysregulation of DYRK-mediated metabolic homeostasis drives the progression of metabolic kidney diseases, key complications of chronic kidney disease. Specifically, DYRK1A aggravates diabetic nephropathy and renal fibrosis; DYRK1B mutations directly trigger mTORC2-mediated lipotoxicity and insulin resistance, promoting glomerulosclerosis; DYRK2 disrupts calcium-phosphorus metabolism and aggravates renal vascular calcification via the Notch/Wnt pathway. DYRK-targeted inhibitors, including harmine, AZ191, and curcumin, have shown therapeutic potential in promoting β-cell regeneration, alleviating metabolic disorders, and suppressing fibrosis. However, insufficient tissue targeting and off-target risks remain critical bottlenecks for clinical translation. Future efforts should integrate gene editing with kidney-specific delivery technologies to enhance therapeutic precision. This review systematically summarizes the structural and functional bases of the DYRK family, its regulatory role in metabolic homeostasis, and its therapeutic prospects in related renal diseases, providing new strategies for precise intervention.</p>","PeriodicalId":74135,"journal":{"name":"MedComm - Future medicine","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mef2.70050","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147568054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The DYRK Family: A Key Regulator of Metabolic Homeostasis and Its Therapeutic Potential in Kidney Diseases","authors":"Yixuan Zhu,&nbsp;Pengfei Qiao,&nbsp;Yukun Gan,&nbsp;Xiushuo Fu,&nbsp;Xiayue Huang,&nbsp;Sirui Sun,&nbsp;Yafei Gou,&nbsp;Wenjie Xia,&nbsp;Feng Ma,&nbsp;Limin Liu","doi":"10.1002/mef2.70050","DOIUrl":"https://doi.org/10.1002/mef2.70050","url":null,"abstract":"<p>The dual-specificity tyrosine-regulated kinase (DYRK) family, a conserved serine/threonine kinase group, plays a pivotal role in the regulation of metabolic homeostasis by modulating glucose/lipid metabolism, oxidative stress, and calcium-phosphorus balance. Mammalian DYRKs are classified into Class I (DYRK1A and DYRK1B) and Class II (DYRK2, DYRK3, and DYRK4) based on their structural differences, tissue-specific expression, and functional diversity in maintaining systemic metabolic balance. Dysregulation of DYRK-mediated metabolic homeostasis drives the progression of metabolic kidney diseases, key complications of chronic kidney disease. Specifically, DYRK1A aggravates diabetic nephropathy and renal fibrosis; DYRK1B mutations directly trigger mTORC2-mediated lipotoxicity and insulin resistance, promoting glomerulosclerosis; DYRK2 disrupts calcium-phosphorus metabolism and aggravates renal vascular calcification via the Notch/Wnt pathway. DYRK-targeted inhibitors, including harmine, AZ191, and curcumin, have shown therapeutic potential in promoting β-cell regeneration, alleviating metabolic disorders, and suppressing fibrosis. However, insufficient tissue targeting and off-target risks remain critical bottlenecks for clinical translation. Future efforts should integrate gene editing with kidney-specific delivery technologies to enhance therapeutic precision. This review systematically summarizes the structural and functional bases of the DYRK family, its regulatory role in metabolic homeostasis, and its therapeutic prospects in related renal diseases, providing new strategies for precise intervention.</p>","PeriodicalId":74135,"journal":{"name":"MedComm - Future medicine","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mef2.70050","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147567754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MicroRNAs in Methamphetamine: Addiction, Neurotoxicity, and Therapeutic Potential","authors":"Yacoubou Abdoul Razak Mahaman,&nbsp;An-Ping Ye,&nbsp;Ya-Xian Zhang,&nbsp;Ming-Yu Chen,&nbsp;Fang Huang,&nbsp;Rong Liu,&nbsp;Ying-Yan Fang,&nbsp;Xiaochuan Wang","doi":"10.1002/mef2.70049","DOIUrl":"https://doi.org/10.1002/mef2.70049","url":null,"abstract":"<p>Drug addiction is a debilitating condition that causes severe mental and physical impairments. Methamphetamine (METH) is one of the most commonly abused psychostimulants, mainly affecting the brain by releasing dopamine and serotonin. METH addiction has become a serious public health issue, and there is currently no specific treatment available. Although scientists have a good understanding of the mechanisms underlying drug addiction, including METH, our current biological and molecular knowledge of addiction is still incomplete. There is substantial evidence that addiction-related changes are primarily mediated through gene expression regulation. Interestingly, the involvement of microRNAs (miRNAs) in this process could enhance our understanding of the molecular mechanisms underlying METH addiction. Therefore, further understanding the mechanisms behind METH-induced differential changes in miRNAs, along with their pharmacological and genetic manipulation, could lead to promising new treatments for METH addiction. In this study, we first summarized epidemiological data and the addictive and neurotoxic mechanisms of METH, extensively reviewed studies on miRNA expression changes, discussed potential miRNA-targeted therapeutic interventions for METH addiction, and outlined future research directions. We believe this study will provide a clearer understanding of the role of miRNAs in METH addiction and may help scientists develop more effective therapeutic strategies.</p>","PeriodicalId":74135,"journal":{"name":"MedComm - Future medicine","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mef2.70049","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147566099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MicroRNAs in Methamphetamine: Addiction, Neurotoxicity, and Therapeutic Potential","authors":"Yacoubou Abdoul Razak Mahaman,&nbsp;An-Ping Ye,&nbsp;Ya-Xian Zhang,&nbsp;Ming-Yu Chen,&nbsp;Fang Huang,&nbsp;Rong Liu,&nbsp;Ying-Yan Fang,&nbsp;Xiaochuan Wang","doi":"10.1002/mef2.70049","DOIUrl":"https://doi.org/10.1002/mef2.70049","url":null,"abstract":"<p>Drug addiction is a debilitating condition that causes severe mental and physical impairments. Methamphetamine (METH) is one of the most commonly abused psychostimulants, mainly affecting the brain by releasing dopamine and serotonin. METH addiction has become a serious public health issue, and there is currently no specific treatment available. Although scientists have a good understanding of the mechanisms underlying drug addiction, including METH, our current biological and molecular knowledge of addiction is still incomplete. There is substantial evidence that addiction-related changes are primarily mediated through gene expression regulation. Interestingly, the involvement of microRNAs (miRNAs) in this process could enhance our understanding of the molecular mechanisms underlying METH addiction. Therefore, further understanding the mechanisms behind METH-induced differential changes in miRNAs, along with their pharmacological and genetic manipulation, could lead to promising new treatments for METH addiction. In this study, we first summarized epidemiological data and the addictive and neurotoxic mechanisms of METH, extensively reviewed studies on miRNA expression changes, discussed potential miRNA-targeted therapeutic interventions for METH addiction, and outlined future research directions. We believe this study will provide a clearer understanding of the role of miRNAs in METH addiction and may help scientists develop more effective therapeutic strategies.</p>","PeriodicalId":74135,"journal":{"name":"MedComm - Future medicine","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mef2.70049","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147566098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitoxyperilysis: A Milestone Discovery in the Field of Cell Death","authors":"Maochen Li,&nbsp;Yuhan Niu,&nbsp;Pengtao Jiao","doi":"10.1002/mef2.70048","DOIUrl":"https://doi.org/10.1002/mef2.70048","url":null,"abstract":"&lt;p&gt;In a recent study published in &lt;i&gt;Cell&lt;/i&gt;, Wang and colleagues unveiled a previously unrecognized form of lytic cell death, termed “mitoxyperilysis,” triggered by mitochondria-induced oxidative damage (Figure 1a) [&lt;span&gt;1&lt;/span&gt;]. This work not only provides critical insights into how mitochondrial dysfunction and oxidative stress drive pathogenesis but also presents a potential strategy for treating oxidative stress-associated diseases.&lt;/p&gt;&lt;p&gt;Metabolic homeostasis is crucial for both cells and organisms, and metabolic dysregulation contributes to diverse pathologies, including cancer, non-alcoholic fatty liver disease, and diabetes [&lt;span&gt;2&lt;/span&gt;]. Innate immune activation and metabolic disruption (IIAMD) often occur simultaneously and jointly drive disease progression. For example, malignant cells undergo metabolic reprogramming characterized by lactate accumulation and hypoxia [&lt;span&gt;3&lt;/span&gt;]. The metabolic alterations promote the release of damage-associated molecular patterns (DAMPs), initiate innate immune pathways (e.g., TLR and NLRP3), and finally lead to various forms of cell death (Figure 1b,c) [&lt;span&gt;2&lt;/span&gt;]. Cell death accompanied by impaired membrane integrity and the release of cellular contents further amplifies inflammatory cascades, establishing a feed-forward loop of DAMP release—inflammation—cell death, ultimately resulting in a pathological state [&lt;span&gt;2&lt;/span&gt;]. Although mitochondrial oxidative stress is implicated in various cell death pathways, the mechanisms by which it drives membrane lysis, particularly under IIAMD, remain poorly understood. This necessitates a deeper investigation into how mitochondrial state dictates cell fate and fuels disease progression.&lt;/p&gt;&lt;p&gt;To mimic IIAMD, Wang Y and colleagues treated bone-marrow-derived macrophages (BMDMs) with innate immune stimulants, including PAM3, LPS, R848, and Poly[I:C] under carbon starvation (CS) [&lt;span&gt;1&lt;/span&gt;]. Interestingly, neither innate immune activation nor CS-induced metabolic stress alone induced cell death. However, in the presence of CS, all stimulants except Poly[I:C] triggered robust lytic cell death, characterized by the release of plasma membrane rupture markers LDH and HMGB1, with LPS exhibiting the strongest effect. Consistently, the supplementation of glucose, glutamine, or pyruvate alone suppressed cell death induced by IIAMD. These findings suggest that innate immune triggering and metabolic stress are necessary and sufficient to induce cell death.&lt;/p&gt;&lt;p&gt;The most disruptive aspect of this work is the unveiling of mitoxyperilysis. To investigate whether cell death under IIAMD is induced by canonical pathways, the genetic ablation of key executioners of apoptosis (e.g., Caspase-9), pyroptosis (e.g., NLRP3 and Gasdermin family members such as GSDMD, GSDME, and GSDMC4), and necroptosis (e.g., MLKL) was performed [&lt;span&gt;1&lt;/span&gt;]. However, the genetic ablation did not markedly attenuate IIAMD-induced membrane rupture. Beyond canonical pathways,","PeriodicalId":74135,"journal":{"name":"MedComm - Future medicine","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mef2.70048","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147562895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitoxyperilysis: A Milestone Discovery in the Field of Cell Death","authors":"Maochen Li,&nbsp;Yuhan Niu,&nbsp;Pengtao Jiao","doi":"10.1002/mef2.70048","DOIUrl":"https://doi.org/10.1002/mef2.70048","url":null,"abstract":"&lt;p&gt;In a recent study published in &lt;i&gt;Cell&lt;/i&gt;, Wang and colleagues unveiled a previously unrecognized form of lytic cell death, termed “mitoxyperilysis,” triggered by mitochondria-induced oxidative damage (Figure 1a) [&lt;span&gt;1&lt;/span&gt;]. This work not only provides critical insights into how mitochondrial dysfunction and oxidative stress drive pathogenesis but also presents a potential strategy for treating oxidative stress-associated diseases.&lt;/p&gt;&lt;p&gt;Metabolic homeostasis is crucial for both cells and organisms, and metabolic dysregulation contributes to diverse pathologies, including cancer, non-alcoholic fatty liver disease, and diabetes [&lt;span&gt;2&lt;/span&gt;]. Innate immune activation and metabolic disruption (IIAMD) often occur simultaneously and jointly drive disease progression. For example, malignant cells undergo metabolic reprogramming characterized by lactate accumulation and hypoxia [&lt;span&gt;3&lt;/span&gt;]. The metabolic alterations promote the release of damage-associated molecular patterns (DAMPs), initiate innate immune pathways (e.g., TLR and NLRP3), and finally lead to various forms of cell death (Figure 1b,c) [&lt;span&gt;2&lt;/span&gt;]. Cell death accompanied by impaired membrane integrity and the release of cellular contents further amplifies inflammatory cascades, establishing a feed-forward loop of DAMP release—inflammation—cell death, ultimately resulting in a pathological state [&lt;span&gt;2&lt;/span&gt;]. Although mitochondrial oxidative stress is implicated in various cell death pathways, the mechanisms by which it drives membrane lysis, particularly under IIAMD, remain poorly understood. This necessitates a deeper investigation into how mitochondrial state dictates cell fate and fuels disease progression.&lt;/p&gt;&lt;p&gt;To mimic IIAMD, Wang Y and colleagues treated bone-marrow-derived macrophages (BMDMs) with innate immune stimulants, including PAM3, LPS, R848, and Poly[I:C] under carbon starvation (CS) [&lt;span&gt;1&lt;/span&gt;]. Interestingly, neither innate immune activation nor CS-induced metabolic stress alone induced cell death. However, in the presence of CS, all stimulants except Poly[I:C] triggered robust lytic cell death, characterized by the release of plasma membrane rupture markers LDH and HMGB1, with LPS exhibiting the strongest effect. Consistently, the supplementation of glucose, glutamine, or pyruvate alone suppressed cell death induced by IIAMD. These findings suggest that innate immune triggering and metabolic stress are necessary and sufficient to induce cell death.&lt;/p&gt;&lt;p&gt;The most disruptive aspect of this work is the unveiling of mitoxyperilysis. To investigate whether cell death under IIAMD is induced by canonical pathways, the genetic ablation of key executioners of apoptosis (e.g., Caspase-9), pyroptosis (e.g., NLRP3 and Gasdermin family members such as GSDMD, GSDME, and GSDMC4), and necroptosis (e.g., MLKL) was performed [&lt;span&gt;1&lt;/span&gt;]. However, the genetic ablation did not markedly attenuate IIAMD-induced membrane rupture. Beyond canonical pathways,","PeriodicalId":74135,"journal":{"name":"MedComm - Future medicine","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mef2.70048","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147562894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ROC-325 Attenuates Hypoxia-Induced Pulmonary Hypertension Through Dual Inhibition of Autophagy and Hypoxia-Inducible Factor 2α Signaling","authors":"Changlei Bao,&nbsp;Shuxin Liang,&nbsp;Dingyuan Liu,&nbsp;Xingting Wang,&nbsp;Dan Bai,&nbsp;Chuangjia Huang,&nbsp;Hanliang Sun,&nbsp;Zi Yang,&nbsp;Bitao Wu,&nbsp;Zixuan Chen,&nbsp;Jieyi Feng,&nbsp;Zinan Luo,&nbsp;Jintao Long,&nbsp;Jinsheng Zhu,&nbsp;June Bai,&nbsp;Li Zhang,&nbsp;Aiai Chu,&nbsp;Caojin Zhang,&nbsp;Haiyang Tang","doi":"10.1002/mef2.70045","DOIUrl":"10.1002/mef2.70045","url":null,"abstract":"<p>The activation of autophagy in endothelial cells is a key mechanism underlying vascular remodeling, leading to the development and progression of pulmonary hypertension (PH). In our previous studies, we developed ROC-325, a novel lysosomal autophagy inhibitor, and demonstrated its potent therapeutic effects in severe pulmonary arterial hypertension (PAH). However, its role in chronic hypoxia-induced PH (HPH) remains unknown. Here, we observed increased LC3B-II/I and decreased p62/SQSTM1 in lung tissues of hypoxic mice, indicative of autophagy activation. ROC-325 treatment suppressed this activation by inhibiting LC3B-II accumulation and restoring p62 levels. ROC-325 significantly reduced right ventricular systolic pressure (RVSP), right ventricular hypertrophy (RVH), and pulmonary artery medial thickening and muscularization, indicating a significantly protective effect against HPH. Endothelial hypoxia-inducible factor 2α (HIF-2α) upregulation, resulting from prolyl hydroxylase domain protein 2 (PHD2) deficiency, was implicated in autophagy activation. Endothelial conditional PHD2 knockout mice, a spontaneous PH model, exhibited elevated LC3B-II/I and HIF-2α levels, both of which were reduced by ROC-325, leading to significant PH attenuation. In vitro, ROC-325 inhibited the proliferation of pulmonary microvascular endothelial cells derived from PHD2-deficient mice and enhanced HIF-2α degradation in human pulmonary artery endothelial cells. These findings, in summary, identify ROC-325 as a promising therapeutic agent for hypoxia-induced PH by modulating both autophagy and endothelial HIF-2α signaling.</p>","PeriodicalId":74135,"journal":{"name":"MedComm - Future medicine","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mef2.70045","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146135958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ROC-325 Attenuates Hypoxia-Induced Pulmonary Hypertension Through Dual Inhibition of Autophagy and Hypoxia-Inducible Factor 2α Signaling","authors":"Changlei Bao,&nbsp;Shuxin Liang,&nbsp;Dingyuan Liu,&nbsp;Xingting Wang,&nbsp;Dan Bai,&nbsp;Chuangjia Huang,&nbsp;Hanliang Sun,&nbsp;Zi Yang,&nbsp;Bitao Wu,&nbsp;Zixuan Chen,&nbsp;Jieyi Feng,&nbsp;Zinan Luo,&nbsp;Jintao Long,&nbsp;Jinsheng Zhu,&nbsp;June Bai,&nbsp;Li Zhang,&nbsp;Aiai Chu,&nbsp;Caojin Zhang,&nbsp;Haiyang Tang","doi":"10.1002/mef2.70045","DOIUrl":"https://doi.org/10.1002/mef2.70045","url":null,"abstract":"<p>The activation of autophagy in endothelial cells is a key mechanism underlying vascular remodeling, leading to the development and progression of pulmonary hypertension (PH). In our previous studies, we developed ROC-325, a novel lysosomal autophagy inhibitor, and demonstrated its potent therapeutic effects in severe pulmonary arterial hypertension (PAH). However, its role in chronic hypoxia-induced PH (HPH) remains unknown. Here, we observed increased LC3B-II/I and decreased p62/SQSTM1 in lung tissues of hypoxic mice, indicative of autophagy activation. ROC-325 treatment suppressed this activation by inhibiting LC3B-II accumulation and restoring p62 levels. ROC-325 significantly reduced right ventricular systolic pressure (RVSP), right ventricular hypertrophy (RVH), and pulmonary artery medial thickening and muscularization, indicating a significantly protective effect against HPH. Endothelial hypoxia-inducible factor 2α (HIF-2α) upregulation, resulting from prolyl hydroxylase domain protein 2 (PHD2) deficiency, was implicated in autophagy activation. Endothelial conditional PHD2 knockout mice, a spontaneous PH model, exhibited elevated LC3B-II/I and HIF-2α levels, both of which were reduced by ROC-325, leading to significant PH attenuation. In vitro, ROC-325 inhibited the proliferation of pulmonary microvascular endothelial cells derived from PHD2-deficient mice and enhanced HIF-2α degradation in human pulmonary artery endothelial cells. These findings, in summary, identify ROC-325 as a promising therapeutic agent for hypoxia-induced PH by modulating both autophagy and endothelial HIF-2α signaling.</p>","PeriodicalId":74135,"journal":{"name":"MedComm - Future medicine","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mef2.70045","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146135959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardiotropic Gene Therapy for Heart Failure: Translational Lessons From AB-1002","authors":"Nghia Phu Nguyen,&nbsp;Phillip Tran","doi":"10.1002/mef2.70046","DOIUrl":"10.1002/mef2.70046","url":null,"abstract":"&lt;p&gt;In a recent study published in &lt;i&gt;Nature Medicine&lt;/i&gt;, Henry et al. [&lt;span&gt;1&lt;/span&gt;] reported the first-in-human trial of AB-1002, a cardiotropic adeno-associated viral (AAV) vector encoding constitutively active inhibitor-1 (I-1c) for the treatment of advanced non-ischemic heart failure. The study demonstrates that a single intracoronary administration of AB-1002 is feasible, well tolerated and provides early evidence that targeted gene therapy may offer a practical translational strategy for restoring cardiac function in patients with limited treatment options.&lt;/p&gt;&lt;p&gt;Heart failure remains a pervasive global challenge, with current therapies largely slowing progression rather than restoring lost myocardial contractile function. The failing heart is characterized by impaired calcium handling, downregulated sarcoplasmic–endoplasmic reticulum calcium ions (Ca&lt;sup&gt;2+&lt;/sup&gt;) ATPase (SERCA2a) pump activity, and maladaptive remodeling that perpetuates systolic dysfunction [&lt;span&gt;2, 3&lt;/span&gt;]. Earlier gene therapy trials, including the CUPID trial targeting SERCA2a, were hindered by limited vector tropism and immune barriers [&lt;span&gt;2, 4&lt;/span&gt;]. Yet advances in capsid engineering and cardiac-specific delivery have reignited the field [&lt;span&gt;3&lt;/span&gt;], culminating in the current clinical translation.&lt;/p&gt;&lt;p&gt;I-1c, the central effector gene in AB-1002, encodes a truncated and constitutively active form of the endogenous protein phosphatase 1 (PP1) inhibitor [&lt;span&gt;3&lt;/span&gt;]. In normal cardiomyocytes, β-adrenergic stimulation phosphorylates phospholamban (PLN) and activates the SERCA2a, enabling calcium reuptake during relaxation [&lt;span&gt;5&lt;/span&gt;]. In heart failure, overactive PP1 dephosphorylates PLN, suppressing SERCA2a and causing cytosolic calcium overload and contractile weakness [&lt;span&gt;5&lt;/span&gt;]. By maintaining PLN phosphorylation, I-1c restores SERCA2a activity, re-establishes Ca&lt;sup&gt;2+&lt;/sup&gt; homeostasis, and improves relaxation and contractility [&lt;span&gt;3, 5&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;Preclinical work demonstrated that cardiac overexpression of I-1c using a re-engineered AAV2/8 vector improved ejection fraction and reduced left-ventricular dilation in a swine model of ischemic heart failure [&lt;span&gt;3&lt;/span&gt;]. These studies laid the foundation for the cardiotropic AAV2i8 vector used in AB-1002—a hybrid of AAV2 and AAV8 sequences designed to enhance myocardial transduction while minimizing hepatic exposure [&lt;span&gt;3&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;In the first-in-human, open-label phase 1 trial [&lt;span&gt;1&lt;/span&gt;], 11 patients with non-ischemic cardiomyopathy, New York Heart Association (NYHA) class III symptoms, and a baseline left ventricular ejection fraction (LVEF) of 15%–35% received a single intracoronary infusion of AB-1002, a chimeric cardiotropic AAV2i8 vector encoding constitutively active inhibitor-1. Two escalating doses were evaluated—3.25 × 10&lt;sup&gt;13&lt;/sup&gt; vg (cohort 1) and 1.08 × 10&lt;sup&gt;14&lt;/sup&gt; vg (cohort 2)—across three study centers in the United States. Participants","PeriodicalId":74135,"journal":{"name":"MedComm - Future medicine","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mef2.70046","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146136673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}