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Viewpoint Collections In-Press Preview Clinical Research and Public Health Research Letters Letters to the Editor Editorials Commentaries Editor's notes Reviews Viewpoints 100th anniversary Top read articles The Journal of Clinical Investigation Current issue Past issues Specialties Reviews Review series Videos ASCI Milestone Awards Video Abstracts Conversations with Giants in Medicine Collections In-Press Preview Clinical Research and Public Health Research Letters Letters to the Editor Editorials Commentaries Editor's notes Reviews Viewpoints 100th anniversary Top read articles Journal Details About Editors Consulting Editors For authors Journal stats Publication ethics Publication alerts by email Advertising Job board Contact Issue published August 3, 2026 Previous issue Volume 136, Issue 15 On the cover: Lymphatic dysfunction linked to Marfan syndrome Show summary Tan et al. report that lymphatic dysfunction and immune cell infiltration contribute to mitral valve disease in a mouse model of Marfan syndrome. The cover art is an illustration highlighting the decreased density of lymphatic vessels (green) within the myxomatous degenerated mitral valve leaflets of a Marfan syndrome mouse model. Image generated using ChatGPT and edited in Adobe Fresco. Image credit: Can Tan. Go to section: ASCI Milestone Award Letter to the Editor Review Series Review Commentaries Research Letter Research Articles Corrigenda ASCI Milestone Award Arul M. Chinnaiyan, MD, PhD, and Charles L. Sawyers, MD, receive the 2026 Harrington Prize for Innovation in Medicine View: Text | PDF Arul M. Chinnaiyan, MD, PhD, and Charles L. Sawyers, MD, receive the 2026 Harrington Prize for Innovation in Medicine Text PDF Abstract Authors Letter to the Editor Could impaired mTORC1 nutrient sensing contribute to obesity-induced thyroid dysfunction? Camila L. Rossetti, Bruna L. Alves, Ernesto Bernal-Mizrachi, Joao Pedro Werneck-de-Castro Camila L. Rossetti, Bruna L. Alves, Ernesto Bernal-Mizrachi, Joao Pedro Werneck-de-Castro View: Text | PDF Could impaired mTORC1 nutrient sensing contribute to obesity-induced thyroid dysfunction? Text PDF Abstract Authors Camila L. Rossetti, Bruna L. Alves, Ernesto Bernal-Mizrachi, Joao Pedro Werneck-de-Castro Review Series The cGAS/STING pathway in cancer: translating innate DNA sensing into therapeutic potential Yi Wang, Juan Angulo-Lozano, Yueqi Wang, Liang Deng Yi Wang, Juan Angulo-Lozano, Yueqi Wang, Liang Deng View: Text | PDF The cGAS/STING pathway in cancer: translating innate DNA sensing into therapeutic potential Text PDF Abstract The cGAS/STING pathway is a central innate immune DNA-sensing system that links aberrant DNA species to innate immune and stress-response transcriptional programs and has emerged as a key regulator of tumor-immune interactions. In cancer, pathway outputs are shaped by interconnected downstream signaling modules, including type I IFN, NF-κB, autophagy, and stress-metabolic checkpoints, as well as by stringent spatial and biochemical regulation of both cGAS and STING. When activation is acute and appropriately compartmentalized, cGAS/STING signaling promotes antitumor immunity across multiple cellular compartments in the tumor microenvironment, supporting DC cross-priming and cytotoxic lymphocyte responses. In contrast, chronic or dysregulated activation rewires downstream signaling toward stress-adaptive and inflammatory programs that promote tumor progression, metastasis, and immune dysfunction, including deleterious effects in lymphocytes and the induction of suppressive myeloid and B cell populations. Here, we examine how context determines the consequences of cGAS/STING activation in cancer, review emerging therapeutic strategies that modulate this pathway, and discuss how its antitumor potential can be maximized while minimizing systemic toxicity and immune dysregulation. Authors Yi Wang, Juan Angulo-Lozano, Yueqi Wang, Liang Deng Review Protein neddylation as a therapeutic target: challenges and opportunities Shizhen Zhang, Huiyin Lan, Yi Sun Shizhen Zhang, Huiyin Lan, Yi Sun View: Text | PDF Protein neddylation as a therapeutic target: challenges and opportunities Text PDF Abstract Protein neddylation is an evolutionarily conserved posttranslational modification that conjugates NEDD8 to its substrate, catalyzed by an E1-activating enzyme, E2-conjugating enzyme, and E3 ligase. Neddylation is essential for cellular homeostasis, and its dysregulation has been implicated in diverse human diseases, including cancer, neurodegenerative diseases, and metabolic disorders, making the process a promising therapeutic target. In this Review, we systematically summarize the biochemical activity and biological functions of neddylation; its alterations in human diseases, particularly in cancers; and its validation as an attractive target for cancer therapy. We provide an overview on the discovery of neddylation inhibitors and the progress of MLN4924 (pevonedistat) and TAS4464 clinical trials and critically evaluate the core challenges and emerging opportunities for therapeutic strategies targeting neddylation. Authors Shizhen Zhang, Huiyin Lan, Yi Sun Commentaries Good cop, bad cop? Rethinking the roles of cardiac macrophages in injury Janmes Karunamurthy, Ziyi Li, Ajitha Thanabalasuriar Janmes Karunamurthy, Ziyi Li, Ajitha Thanabalasuriar View: Text | PDF Good cop, bad cop? Rethinking the roles of cardiac macrophages in injury Text PDF Abstract Cardiac macrophages (CMs) preserve homeostasis in the heart by clearing cellular debris and facilitating electrical conduction. During tissue injury, embryonically derived CMs (em-CMs) have traditionally been deemed beneficial for promoting tissue repair, whereas monocyte-derived CMs (mo-CMs) are considered detrimental, contributing to inflammation and tissue damage. However, Kasam et al. challenge this binary classification using cardiac-specific strategies to expand either em-CM or mo-CM populations. As expected, mice with cardiac-specific mo-CM expansion exhibited adverse outcomes following transverse aortic constriction (TAC). Surprisingly, mice with expanded em-CMs also showed a marked decline in cardiac function after TAC, which was associated with an unexpected interaction with mo-CMs. This deterioration was temporally regulated, occurring only if em-CMs were expanded before TAC induction. Together, these findings suggest that simplistic classification of CMs as either beneficial or harmful underestimates their complex roles in cardiac pathology, highlighting the need to reassess current views of macrophage function in heart injury. Authors Janmes Karunamurthy, Ziyi Li, Ajitha Thanabalasuriar Lymphatic therapies open the valve in Marfan syndrome Yanna Tian, Kathleen M. Caron Yanna Tian, Kathleen M. Caron View: Text | PDF Lymphatic therapies open the valve in Marfan syndrome Text PDF Abstract Myxomatous degeneration of the mitral valve (MDMV) is a common cardiovascular manifestation of Marfan syndrome (MFS), yet the role of lymphatic vessels in the disease progression remains unknown. In this Commentary, we discuss the study by Tan, Kume, and colleagues, which identifies defective lymphangiogenesis as a previously unrecognized driver of MDMV. Their work demonstrates that impaired lymphatic development and drainage promote valve inflammation through reduced ZFP36-mediated antiinflammatory signaling, whereas restoration of lymphatic function or pharmacological activation of ZFP36 with the FDA-approved drug FTY720 ameliorates disease progression. These findings establish lymphatic vessels as critical regulators of mitral valve homeostasis and support exploration of lymphatic-targeted therapeutic opportunities for MFS-associated valvular disease. Authors Yanna Tian, Kathleen M. Caron Diabetic and ER-stressed pancreatic islet β cells are in need of some JNK removal Jonathan M. Palozzi, Pere Puigserver Jonathan M. Palozzi, Pere Puigserver View: Text | PDF Diabetic and ER-stressed pancreatic islet β cells are in need of some JNK removal Text PDF Abstract Pancreatic β cells regulate glucose homeostasis through insulin secretion, but nutrient overload and genetic defects can trigger ER stress and apoptosis, contributing to type 2 diabetes. Within β cells, the kinases PERK, IRE1α, and ATF6 initiate the unfolded protein response (UPR) as a result of ER stress, a process that is constitutively suppressed under nonstress conditions by GRP78 binding to these proteins. To gain insight into the mechanisms of β cell death upon dysregulated ER stress, Sharma et al. used β cell–specific GRP78 knockout models, revealing that hyperactivation of the UPR promoted β cell death primarily through the IRE1α/JNK/p53 signaling pathway. Pharmacological inhibition of JNK improved β cell survival, increased insulin levels, and lowered blood glucose in multiple diabetic mouse models. These findings highlight JNK signaling as a promising therapeutic target for preserving β cell function. Authors Jonathan M. Palozzi, Pere Puigserver Research Letter LINGO1-targeted antibody-drug conjugates improve efficacy and tolerability of antineoplastic therapies in Ewing sarcoma models Zhichuan Zhu, Yusha Liu, Yu Deng, Zhijun Li, Albert S. Baldwin, Pengda Liu Zhichuan Zhu, Yusha Liu, Yu Deng, Zhijun Li, Albert S. Baldwin, Pengda Liu View: Text | PDF LINGO1-targeted antibody-drug conjugates improve efficacy and tolerability of antineoplastic therapies in Ewing sarcoma models Text PDF Abstract Authors Zhichuan Zhu, Yusha Liu, Yu Deng, Zhijun Li, Albert S. Baldwin, Pengda Liu Research Articles JNK and p53 cause human and mouse β cell death during excessive unfolded protein response Rohit B. Sharma, Christine Darko, Ying Wang, Thalia A. Castro, Tara Doma Lama, Brian Gablaski, Andrew Rappa, David Redmond, Jason K. Kim, Amy S. Lee, Laura C. Alonso Rohit B. Sharma, Christine Darko, Ying Wang, Thalia A. Castro, Tara Doma Lama, Brian Gablaski, Andrew Rappa, David Redmond, Jason K. Kim, Amy S. Lee, Laura C. Alonso View: Text | PDF JNK and p53 cause human and mouse β cell death during excessive unfolded protein response Text PDF Abstract Endoplasmic reticulum (ER) stress contributes to β cell death in both Type 1 and Type 2 diabetes (T1D and T2D). However, the molecular mechanisms driving β cell death during ER stress remain insufficiently defined, limiting development of protective therapies. GRP78, an ER chaperone, is the master regulator of unfolded protein response (UPR), suppressing UPR initiators during the unstressed state and releasing them to allow UPR activation during stress. To dissect the pathways leading to ER-stress response related β cell decompensation, we engineered mice genetically lacking GRP78 in pancreatic β cells. GRP78 deletion caused acute insulin-deficient diabetes in pups before weaning, with reduced β cell mass due to increased apoptosis. Molecular studies identified deregulated UPR, specifically IRE1 activity, as driving cell death. Unbiased and targeted analyses identified a JNK-p53 axis downstream of IRE1 kinase as a key medi…