Drug Design, Development and Therapy最新文献

{"title":"Effect of a Single Subanesthetic Dose of Esketamine on Gastrointestinal Recovery After Laparoscopic Colorectal Cancer Surgery: A Randomized, Outcome-Assessor-Blinded, Placebo-Controlled Trial.","authors":"Zhenye Zhang, Jun Liu, Ping Xiang, Yawei Feng, Xiaomin Chen, Xingmin Li, Ziqing Hei, Xiang Li","doi":"10.2147/DDDT.S644802","DOIUrl":"10.2147/DDDT.S644802","url":null,"abstract":"<p><strong>Purpose: </strong>Postoperative gastrointestinal dysfunction (POGD) and Postoperative gastrointestinal intolerance (POGI) remain a critical challenge in abdominal surgery, particularly for colorectal cancer patients undergoing laparoscopic procedures. Current evidence suggests anesthetic agents may influence gastrointestinal recovery, yet the impact of esketamine remains underexplored. This trial aimed to investigate whether intraoperative esketamine administration accelerates gastrointestinal function recovery.</p><p><strong>Methods: </strong>In this single-center, randomized, outcome-assessor -blind trial, 104 patients (aged 18-75, ASA I-III) scheduled for elective laparoscopic colorectal cancer surgery were allocated to receive either intravenous esketamine (0.2 mg/kg) or saline (control) 30 minutes before surgery completion. Primary outcome was time to first flatus; secondary outcomes included I-FEED scores, defecation time, oral intake tolerance, and postoperative complications assessed within seven days after surgery.</p><p><strong>Results: </strong>The esketamine group demonstrated significantly shorter time to first flatus (52 [50.25-53.75] vs 60 [58.59-61.41] hours; P < 0.001) and first defecation (87 [81.96-92.04] vs 95 [92.65-97.35] hours; P = 0.04) compared to controls. I-FEED scores were markedly lower (median 1 [0.25-2] vs 2.5 [1-3]; P < 0.001), with reduced nausea (P = 0.001) and abdominal distension duration (P < 0.001). Esketamine also improved postoperative sleep quality, but did not affect hospitalization costs or length of stay.</p><p><strong>Conclusion: </strong>Intraoperative esketamine accelerates gastrointestinal function recovery after laparoscopic colorectal surgery, especially reducing postoperative gastrointestinal intolerance symptoms of nausea and distension while improving early sleep quality. However, no evident benefit was observed in reducing hospital length of stay or patient costs.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"644802"},"PeriodicalIF":6.1,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13654259/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149165830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug Delivery Systems for Hepatocellular Carcinoma: Bridging Pathophysiological Barriers and Advanced Nanomedicine Strategies.","authors":"Guiwen Liang, Chuli Zhu, Hualin Sun, Jiahuan Gong, Yanan Ji, Lei Qi","doi":"10.2147/DDDT.S630797","DOIUrl":"https://doi.org/10.2147/DDDT.S630797","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is characterized by high heterogeneity, a complex tumor microenvironment, and multiple physiological barriers that limit conventional therapies and cause significant toxicity. Drug delivery systems (DDS), particularly nanoscale delivery systems, offer promising opportunities to overcome these obstacles through passive targeting, active targeting, and stimuli-responsive drug release. Nevertheless, despite substantial progress in preclinical research, the clinical translation of most DDS remains challenging. This review systematically outlines the pathophysiological rationale underpinning DDS design for HCC, including the aberrant vasculature, hypoxia, low pH, overexpressed enzymes and immunosuppressive features of the TME, as well as liver-specific barriers. Subsequently, we comprehensively evaluate the progress and limitations of passive targeting, active targeting, stimuli-responsive, and locoregional delivery systems. Furthermore, we dissect the core bottlenecks currently impeding clinical translation: tumor heterogeneity, the \"interlocking chain\" effect of multiple biological barriers, uncertainty of the EPR effect, multidrug resistance mechanisms, poorly defined long-term safety of nanocarriers, and the \"valley of death\" caused by discrepancies between preclinical models and human disease. Finally, we envision future directions: next-generation targeting strategies should focus on CSCs and metastasis; DDS must be deeply integrated with immunotherapy to remodel the immune microenvironment; biomimetic and bio-derived delivery systems may circumvent inherent limitations of synthetic carriers; multifunctional theranostic platforms enable real-time monitoring and personalized treatment; and establishing more clinically relevant animal models alongside personalized DDS design paradigms is key to accelerating translation. Our central argument is that the future success of DDS for HCC will no longer rely on the \"showmanship\" of individual technologies, but rather on a \"systems engineering\" approach grounded in a profound understanding of HCC biological heterogeneity, with the core objectives being precise spatiotemporal control of drug distribution and beneficial interactions with the host immune system.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"630797"},"PeriodicalIF":6.1,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13654291/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149169631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Temporal Alignment and Validation in Machine-Learning Prediction of Secondary Loss of Response to Infliximab [Letter].","authors":"Zeming Qiu, Xueyan Xia, Xiancheng Li","doi":"10.2147/DDDT.S658245","DOIUrl":"https://doi.org/10.2147/DDDT.S658245","url":null,"abstract":"","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"658245"},"PeriodicalIF":6.1,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13653511/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential Relevance of <i>Bidens pilosa</i> L. to Atopic Dermatitis: Mechanistic Evidence, Drug Development Challenges, and Future Perspectives.","authors":"Iyan Sopyan, Endang Lukitaningsih, Rachmat Mauludin, Sani Ega Priani, Virginia Heaven Mariboto Siagian, Johnessa Cung, Muhammad Syahrul, Miranda Cania Sirait","doi":"10.2147/DDDT.S642169","DOIUrl":"https://doi.org/10.2147/DDDT.S642169","url":null,"abstract":"<p><p>Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by epidermal barrier dysfunction, immune dysregulation, oxidative stress, microbial dysbiosis, and persistent inflammation. Although current therapies have improved disease management, long-term treatment remains challenging because of disease relapse, adverse effects, treatment costs, and variability in therapeutic response. These challenges have stimulated interest in botanical agents with diverse phytochemical profiles and potentially complementary biological activities. <i>Bidens pilosa</i> L. has attracted attention because of its diverse phytochemical composition and reported anti-inflammatory, antioxidant, antibacterial, and immunomodulatory activities. This narrative review integrates phytochemical, pharmacological, computational, safety, and pharmaceutical evidence to examine the potential relevance of <i>B. pilosa</i> to AD and the challenges associated with its further development. Available evidence indicates that <i>B. pilosa</i>-derived preparations and individual phytoconstituents exhibit multiple biological activities relevant to inflammatory, oxidative, immune, and microbial processes involved in AD. While most pharmacological studies of <i>B. pilosa</i> have been conducted in general inflammatory or non-dermatological models, several AD-relevant studies of individual phytoconstituents reported in <i>B. pilosa</i> provide additional mechanistic support. Computational studies further suggest potential interactions between selected phytoconstituents and AD-related molecular targets, providing hypotheses for further experimental investigation. Overall, the available evidence supports the potential relevance of <i>B. pilosa</i> to AD and provides a rationale for further development, while recognizing the need for greater validation of standardized preparations in AD-specific models. Future studies should prioritize phytochemical standardization, validated AD models, dermal safety assessment, topical formulation development, and clinical evaluation.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"642169"},"PeriodicalIF":6.1,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13653635/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From Mechanistic Evidence to Clinical Translation: A Narrative Review of Chinese Herbal Medicine for Insomnia.","authors":"Ximing Li, Hanying Xu, Ying Zhang, Jing Lu, Yibin Zhang, Lin Zhang, Lan Yu, Hongmei Nan","doi":"10.2147/DDDT.S642176","DOIUrl":"https://doi.org/10.2147/DDDT.S642176","url":null,"abstract":"<p><p>Insomnia is one of the most common sleep disorders and a major public health problem worldwide. Chinese herbal medicine (CHM) is widely used as a complementary and alternative approach for chronic insomnia. Clinical studies have reported preliminary evidence of benefit for Chinese herbal formulas, whereas mechanistic research has examined single herbs, extracts, active constituents, and compound formulas using multi-omics analysis, network pharmacology, molecular prediction, and experimental validation. However, clinical studies are typically small and of inconsistent methodological quality, with limited long-term follow-up, while mechanistic evidence remains fragmented and lacks systematic integration and translational validation. These limitations restrict the development of CHM interventions from experimental evidence to clinically testable interventions for insomnia. This narrative review evaluates existing research across five translational dimensions, namely chemical characterization and preparation quality, exposure and pharmacodynamic evidence, mechanism and target validation, sleep-related clinical endpoints, and safety. It aims to clarify the current state of research on CHM interventions for insomnia and to identify key limitations and priorities for future research. Most available evidence comes from preclinical studies, which suggest that CHM may influence sleep-related processes through γ-aminobutyric acid (GABA) and serotonergic signaling, the hypothalamic-pituitary-adrenal (HPA) axis, neuroinflammation, oxidative stress, apoptosis-autophagy balance, and the brain-gut-microbiota axis. Much of this evidence reflects changes in biochemical markers or pathway activity, while only a few studies directly test target function. Clinical studies provide preliminary evidence of short-term improvements in subjective sleep outcomes. However, clinical translation remains limited by insufficient evidence for objective sleep improvement and long-term efficacy and safety. Future work should carry a few well-characterized interventions through the full evidence chain, prioritizing standardized preparations, exposure and pharmacodynamic assessment, objective sleep endpoints, long-term follow-up, and safety.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"642176"},"PeriodicalIF":6.1,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13653551/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149165226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methodological Considerations on the Cumulative Folic Acid Dose Threshold and Incident Diabetes in Coronary Heart Disease [Letter].","authors":"Jiaying Li, Ning Li","doi":"10.2147/DDDT.S657868","DOIUrl":"https://doi.org/10.2147/DDDT.S657868","url":null,"abstract":"","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"657868"},"PeriodicalIF":6.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651742/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanisms and Application Strategies of Flavonoid Active Compounds in the Treatment of Osteoporosis-Osteoarthritis Comorbidity: Insights from Preclinical Studies.","authors":"Xingwen Xie, Yandong Liu, Yanjun Zhang, Peng Qi, Xudong Chang, Xianfu Han, Jianqiang Du","doi":"10.2147/DDDT.S637977","DOIUrl":"https://doi.org/10.2147/DDDT.S637977","url":null,"abstract":"<p><p>Osteoporosis (OP) and osteoarthritis (OA) are two prevalent age-related musculoskeletal disorders that frequently coexist in elderly populations, substantially complicating clinical diagnosis and treatment. In recent years, flavonoid active compounds have attracted increasing research interest for OP-OA comorbidity owing to their multitargeted pharmacological activities and generally favorable safety profiles, although current evidence remains largely limited to preclinical in vitro and animal studies. This review systematically summarizes the chemical classification, natural sources and pharmacokinetic profiles of flavonoids, and dissects the pathophysiological crosstalk underlying OP-OA comorbidity, focusing on core cascades including estrogen deficiency, chronic inflammation, oxidative stress and dysregulation of shared signaling pathways. We collate preclinical evidence from animal models and cell experiments regarding representative flavonoids (icariin, quercetin, liquiritigenin, soy isoflavones, and others) for concurrent OP and OA, and delineate their molecular mechanisms: modulation of antioxidant and anti-inflammatory responses; balancing bone metabolism via OPG/RANKL/RANK, PI3K/Akt and Wnt/beta-catenin axes; attenuating cartilage degeneration and intra-articular inflammation; and multitargeted regulation of MAPK, NF-kappaB and Hippo pathways. Key findings indicate that flavonoids exert preclinical protective effects through coordinated modulation of shared pathological axes, yet several critical gaps remain: effective in vitro concentrations (25-100 microM) far exceed achievable in vivo plasma levels, most evidence derives from single-disease rather than bona fide comorbidity models, and high-quality clinical trials are lacking. Strategies including bioavailability enhancement, bone- or joint-targeted nanodelivery, and combinatorial regimens are discussed as avenues to bridge these gaps. Flavonoids show promising preclinical potential for OP-OA comorbidity; however, their efficacy and safety require further validation in standardized comorbidity animal models, high-quality pharmacokinetic studies, and well-designed clinical trials before clinical application can be recommended.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"637977"},"PeriodicalIF":6.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651737/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149166623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Perioperative Intravenous Lidocaine on Rebound Pain After Interscalene Brachial Plexus Block for Arthroscopic Rotator Cuff Repair: A Randomized Placebo-Controlled Trial.","authors":"Baozhou Zhang, Yifan Liu, Jinwei Zheng","doi":"10.2147/DDDT.S643996","DOIUrl":"10.2147/DDDT.S643996","url":null,"abstract":"<p><strong>Background: </strong>Rebound pain after single-shot interscalene brachial plexus block may diminish the early analgesic benefit of regional anesthesia after shoulder arthroscopy. We evaluated whether perioperative intravenous lidocaine reduces rebound pain after arthroscopic rotator cuff repair.</p><p><strong>Methods: </strong>In this single-center randomized, placebo-controlled Phase II trial, 120 adults receiving interscalene block plus general anesthesia were allocated 1:1 to saline or lidocaine. Lidocaine was given as a 1 mg/kg ideal-body-weight loading dose before induction followed by 2 mg·kg^-1·h^-1 from skin incision to closure. The primary outcome was rebound pain within 24 hours.</p><p><strong>Results: </strong>Rebound pain occurred in 14/60 participants (23.3%) with lidocaine and 22/60 (36.7%) with saline [risk difference -13.3%, 95% confidence interval (CI) -28.8% to 3.1%; relative risk 0.64, 95% CI 0.36-1.12; P = 0.163]. Median peak movement-evoked numerical rating scale scores were 5 in both groups (P = 0.136). The mean intraoperative remifentanil infusion rate was lower with lidocaine (mean difference -81.67 μg/h, 95% CI -101.47 to -61.86; P < 0.001). Baseline-adjusted discharge University of California, Los Angeles (UCLA) Shoulder Scores were higher and postoperative 9-item Central Sensitization Inventory (CSI-9) scores were lower with lidocaine (both P < 0.001); these outcomes were exploratory. Although 60 participants per group were enrolled, a corrected post hoc calculation indicated that approximately 82 evaluable participants per group were required for the prespecified effect. The lower composite adverse-event rate was mainly attributable to less propofol injection pain.</p><p><strong>Conclusion: </strong>This trial did not establish a statistically significant reduction in 24-hour rebound pain with perioperative intravenous lidocaine. Because the study was potentially underpowered, a clinically meaningful effect cannot be excluded. Lidocaine was associated with a lower mean intraoperative remifentanil infusion rate, whereas other recovery findings were exploratory. Larger adequately powered trials are needed before lidocaine can be recommended to prevent rebound pain.</p><p><strong>Trial registration: </strong>Chinese Clinical Trial Registry, ChiCTR2500103951; registered June 9, 2025. Registry record: https://www.chictr.org.cn/hvshowproject.html?id=278342andv=1.0.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"643996"},"PeriodicalIF":6.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13653266/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149165431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Remimazolam ED95 for Preoperative Sedation in Children with Obstructive Sleep Apnea, with Obesity or a Reference-Range BMI: A Biased-Coin Dose-Finding Study.","authors":"Fan Xiao, Tingyu Zhao, Cheng Xu, Jun Yao, Rong Wei, Yan Jiang","doi":"10.2147/DDDT.S645102","DOIUrl":"10.2147/DDDT.S645102","url":null,"abstract":"<p><strong>Background: </strong>Obesity may alter total-body-weight dosing of remimazolam, whereas obstructive sleep apnea narrows the respiratory safety margin. We estimated the ED95 for protocol-defined preoperative sedation in children with obesity or a reference-range body mass index (BMI).</p><p><strong>Methods: </strong>In this prospective, single-center sequential dose-finding study, 80 children aged 3-17 years with a clinical OSA diagnosis undergoing adenoidectomy and/or tonsillectomy entered study-defined obesity (BMI-for-age >95th percentile) or reference-BMI (25th-84th percentile) groups (40 each). Independent biased-coin sequences used total-body-weight doses, starting at 0.20 mg/kg with 0.05 mg/kg steps. The response was a Ramsay Sedation Scale (RSS) score ≥4 at 3 minutes after completion of a 1-minute intravenous bolus. Isotonic regression and 2000 bootstrap resamples yielded ED95 estimates and bias-corrected percentile 95% confidence intervals (CIs).</p><p><strong>Results: </strong>Responses occurred in 35/40 (87.5%) participants in the obesity group and 34/40 (85.0%) in the reference-BMI group. ED95 estimates were 0.38 mg/kg (95% CI, 0.32-0.39) and 0.44 mg/kg (95% CI, 0.39-0.44), respectively. The difference was -0.05 mg/kg (95% CI, -0.13 to 0.05). During 15-minute observation, one child per group developed hypoxemia (SpO2 93%) that resolved after a jaw-thrust maneuver. One reference-BMI participant developed bradycardia (50 beats/min), which responded to atropine. No child had a ≥30% decrease in mean arterial pressure.</p><p><strong>Conclusion: </strong>The protocol-specific ED95 values of a 1-min remimazolam bolus for RSS ≥4 at 3 min were 0.38 mg/kg in children with obesity and 0.44 mg/kg in children with a reference-range BMI.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"645102"},"PeriodicalIF":6.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651723/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bidirectional Crosstalk Between cGAS-STING and Necroptosis: From Mitochondrial DNA Release to Inflammatory Disease.","authors":"Hongquan Wang, Zhiji Wang, Hui Zhang, Zhihang Yang, Shuang Zhao, Yuzi Jin","doi":"10.2147/DDDT.S649776","DOIUrl":"https://doi.org/10.2147/DDDT.S649776","url":null,"abstract":"<p><p>The cGAS-STING pathway, a cornerstone of cytosolic DNA sensing, and necroptosis, a pro-inflammatory regulated cell death modality, are increasingly recognized as intimately interconnected axes that profoundly influence disease pathogenesis. This review synthesizes current knowledge on their bidirectional crosstalk, emphasizing the molecular underpinnings and therapeutic implications. We detail how cGAS -STING activation can precipitate necroptosis through type I interferon and TNF-α synergy, as well as transcriptional upregulation of ZBP1, with mitochondrial damage and mtDNA release serving as critical upstream triggers. Reciprocally, in certain necroptotic settings, phosphorylated MLKL can permeabilize mitochondrial membranes to liberate mtDNA, although this is not yet established as an obligatory feature of all MLKL-dependent necroptosis, which activates cGAS-STING independently of plasma membrane rupture, while RIPK3 can drive mitochondrial dysfunction to similar effect. This reciprocal engagement often escalates into a self-amplifying feedback loop that drives chronic inflammation and tissue injury across diverse pathologies, including neurodegenerative disorders, sterile organ injury, and cancer, though it can also be harnessed for antitumor immunity. However, this crosstalk is context-dependent rather than uniformly amplifying: in some settings, STING activation restrains necroptosis, as observed during <i>Staphylococcus aureus</i> pneumonia and in human monocytes. The review further evaluates emerging pharmacological strategies that target this interface, ranging from direct inhibitors of STING or MLKL to agents that preserve mitochondrial integrity, and discusses the context-dependent challenges of therapeutic intervention. By framing the cGAS -STING-necroptosis axis as a central hub integrating innate immune sensing with inflammatory cell death, we underscore its significant potential as a therapeutic target for inflammation-associated diseases.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"649776"},"PeriodicalIF":6.1,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651800/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149165350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}