Ischemic stroke is caused primarily by an interruption in cerebral blood flow, which induces severe neural injuries, and is one of the leading causes of death and disability worldwide. Thus, it is of great necessity to further detailly elucidate the mechanisms of ischemic stroke and find out new therapies against the disease. In recent years, efforts have been made to understand the pathophysiology of ischemic stroke, including cellular excitotoxicity, oxidative stress, cell death processes, and neuroinflammation. In the meantime, a plethora of signaling pathways, either detrimental or neuroprotective, are also highly involved in the forementioned pathophysiology. These pathways are closely intertwined and form a complex signaling network. Also, these signaling pathways reveal therapeutic potential, as targeting these signaling pathways could possibly serve as therapeutic approaches against ischemic stroke. In this review, we describe the signaling pathways involved in ischemic stroke and categorize them based on the pathophysiological processes they participate in. Therapeutic approaches targeting these signaling pathways, which are associated with the pathophysiology mentioned above, are also discussed. Meanwhile, clinical trials regarding ischemic stroke, which potentially target the pathophysiology and the signaling pathways involved, are summarized in details. Conclusively, this review elucidated potential molecular mechanisms and related signaling pathways underlying ischemic stroke, and summarize the therapeutic approaches targeted various pathophysiology, with particular reference to clinical trials and future prospects for treating ischemic stroke.

Endovascular therapy is the first-line treatment for acute ischemic stroke. However, studies have shown that, even with the timely opening of occluded blood vessels, nearly half of all patients treated with endovascular therapy for acute ischemic stroke still have poor functional recovery, a phenomenon called “futile recanalization.”. The pathophysiology of futile recanalization is complex and may include tissue no-reflow (microcirculation reperfusion failure despite recanalization of the occluded large artery), early arterial reocclusion (reocclusion of the recanalized artery 24-48 hours post endovascular therapy), poor collateral circulation, hemorrhagic transformation (cerebral bleeding following primary ischemic stroke), impaired cerebrovascular autoregulation, and large hypoperfusion volume. Therapeutic strategies targeting these mechanisms have been attempted in preclinical research; however, translation to the bedside remains to be explored. This review summarizes the risk factors, pathophysiological mechanisms, and targeted therapy strategies of futile recanalization, focusing on the mechanisms and targeted therapy strategies of no-reflow to deepen the understanding of this phenomenon and provide new translational research ideas and potential intervention targets for improving the efficacy of endovascular therapy for acute ischemic stroke.

Immune-mediated necrotizing myopathy (IMNM) is an autoimmune disorder associated with the presence of autoantibodies, characterized by severe clinical presentation with rapidly progressive muscular weakness and elevated levels of creatine kinase, while traditional pharmacological approaches possess varying and often limited effects. Considering the pathogenic role of autoantibodies, chimeric antigen receptor (CAR)-T cells targeting B cell maturation antigen (BCMA) have emerged as a promising therapeutic strategy. We reported here a patient with anti-signal recognition particle IMNM refractory to multiple available therapies, who was treated with BCMA-targeting CAR-T cells, exhibited favorable safety profiles, sustained reduction in pathogenic autoantibodies, and persistent clinical improvements over 18 mo. Longitudinal single-cell RNA, B cell receptor, T cell receptor sequencing analysis presented the normalization of immune microenvironment after CAR-T cell infusion, including reconstitution of B cell lineages, replacement of T cell subclusters, and suppression of overactivated immune cells. Analysis on characteristics of CAR-T cells in IMNM demonstrated a more active expansion of CD8 ⁺ CAR-T cells, with a dynamic phenotype shifting pattern similar in CD4 ⁺ and CD8 ⁺ CAR-T cells. A comparison of CD8 ⁺ CAR-T cells in patients with IMNM and those with malignancies collected at different timepoints revealed a more NK-like phenotype with enhanced tendency of cell death and neuroinflammation and inhibited proliferating ability of CD8 ⁺ CAR-T cells in IMNM while neuroinflammation might be the distinct characteristics. Further studies are warranted to define the molecular features of CAR-T cells in autoimmunity and to seek higher efficiency and longer persistence of CAR-T cells in treating autoimmune disorders.

Chimeric antigen receptor (CAR) T cell immunotherapy for the treatment of neurological autoimmune diseases is promising, but CAR T cell kinetics and immune alterations after treatment are poorly understood. Here, we performed single-cell multi-omics sequencing of paired cerebrospinal fluid (CSF) and blood samples from patients with neuromyelitis optica spectrum disorder (NMOSD) treated with anti–B cell maturation antigen (BCMA) CAR T cells. Proliferating cytotoxic-like CD8 ⁺ CAR T cell clones were identified as the main effectors in autoimmunity. Anti-BCMA CAR T cells with enhanced features of chemotaxis efficiently crossed the blood-CSF barrier, eliminated plasmablasts and plasma cells in the CSF, and suppressed neuroinflammation. The CD44-expressing early memory phenotype in infusion products was potentially associated with CAR T cell persistence in autoimmunity. Moreover, CAR T cells from patients with NMOSD displayed distinctive features of suppressed cytotoxicity compared with those from hematological malignancies. Thus, we provide mechanistic insights into CAR T cell function in patients with neurological autoimmune disease.

Revascularization and angiogenesis, as substrates of sustained collateral circulation, play a crucial role in determining the severity and clinical outcome of acute ischemic stroke (AIS) due to large vessel occlusion (LVO). Developing an adjunct biomarker to help identify and monitor collateral status would aid stroke diagnosis and prognosis. To screen the potential biomarkers, proteomic analysis was performed in this study to identify those distinct plasma protein profiles in AIS due to LVO with different collateral status. Interestingly, we found that levels of Plasma Factor VII Activating Protease (FSAP) significantly increased in those AIS patients with poor collaterals, and were correlated with worse neurological outcome. Furtherly, both in vitro and in vivo models of ischemic stroke were used to explore pathological mechanisms of FSAP in endothelial dysfunction. We demonstrated that the FSAP inhibitor, high-molecular-weight hyaluronan (HMW-HA), enhanced the pro-angiogenic vascular factors, improved the integrity of brain blood barrier, and promoted newly formed cerebral microvessels in the ischemic penumbra, consequently improving neurological function. To elucidate the pathways that might contribute to revascularization during LVO, we applied transcriptomic analysis via unbiased RNA sequencing and showed that Wnt signaling was highly involved in FSAP mediated endothelial dysfunction. Notably, inhibition of Wnt5a largely reversed the protective effects from HMW-HA treatment, implying that FSAP might aggravate endothelial dysfunction and neurological deficits by regulating Wnt5a signaling. Therefore, FSAP may represent a potential biomarker for collateral status after LVO and a promising therapeutic target to be explored in the treatment of stroke.