Trends in molecular medicine最新文献

Huntington's disease (HD) is usually described as rare, tragic, and intractable. Yet, HD offers a strategically unique entry point for neuroscience. With its genetic clarity, relatively predictable course, and organized global community, HD provides the clearest path to advancing brain repair.

The muscle regeneration niche comprises various cell types, including muscle stem cells (MuSCs; also termed satellite cells), immune cells, and stromal cells, all of which have crucial roles in the regeneration process. Intracellular metabolic reprogramming during injury responses is closely linked to the functional activities of these cells, thus necessitating a comprehensive understanding for developing targeted metabolic interventions that promote regeneration. Recent studies have suggested the existence of a more intricate network, involving cell-cell metabolic crosstalk and even cross-organ regulation, which underpins muscle regeneration. In addition, aging and diseases that disrupt overall metabolic homeostasis contribute to muscle dysfunction, due, in part, to metabolic disorders in the regeneration niche. In this review, we provide a comprehensive overview of the metabolic profile within the muscle regeneration niche and highlight potential interventions to reprogram metabolism to improve regenerative capacity.

Ferroptosis, a regulated cell death pathway driven by iron-catalyzed lipid peroxidation, has recently been implicated as a major cause of hepatic injury in metabolic dysfunction-associated fatty liver disease (MAFLD). This review highlights how the identification of hyperoxidized peroxiredoxin 3 (PRDX3) as a ferroptosis-specific marker has led to the discovery that ferroptosis contributes to liver injury in MAFLD, and summarizes other emerging evidence connecting ferroptosis to MAFLD pathogenesis. These new findings suggest that dietary fat composition and genetic variants such as PNPLA3(I148M) may affect the progression of MAFLD by regulating cellular sensitivity to ferroptosis. Recognizing MAFLD as a ferroptotic disease provides novel insights into the pathogenesis of the disease, and supports the exploration of ferroptosis as a potential target for therapeutic intervention.

Cachexia and hypercalcemia frequently complicate advanced renal cancer. A recent Nature Medicine study by Abu-Remaileh et al. shows that pharmacologic hypoxia-inducible factor 2 (HIF2) inhibition rapidly suppresses parathyroid hormone-related protein (PTHrP), reverses metabolic wasting, and normalizes calcium levels, redefining these paraneoplastic syndromes as targetable endocrine disorders rather than secondary consequences of tumor burden.

Dysregulation of the RAF-MEK-ERK1/2 pathway is involved in the pathoetiology of many diseases. Its central role in cancer has led to the development of drugs targeting upstream receptors, RAS, and kinases in the extracellular signal-regulated kinase 1 (ERK1) and 2 (ERK2) signaling cascade. The use of these drugs in cancer therapy - together with ongoing monitoring of their effectiveness, evolving side-effects, and resistance mechanisms - has expanded our knowledge of both the physiological and pathological functions of ERK1/2 and could thus provide potential alternative therapeutic strategies. In this review we discuss the latest insights into targeting of MEK1/2 and ERK1/2 and the transfer of the lessons learned from cancer treatment to further indications involving ERK1/2 dysregulation such as genetic disorders (RASopathies) and beyond.

In recent years, numerous studies have highlighted the crucial role of mitochondrial metabolism in cancer progression. This sparked interest in its potential as a target for cancer therapy and prompted the clinical evaluation of multiple drugs targeting mitochondrial metabolism. Regrettably, most have showed limited efficacy and safety, raising concerns about the viability of mitochondrial inhibitors in cancer treatment. However, emerging evidence suggests that shifting the focus away from mitochondrial bioenergetics and targeting other aspects of mitochondrial biology, may have a meaningful impact on cancer progression with milder side effects. In this review, we discuss emerging actionable targets and strategies to tailor the administration of inhibitors of mitochondrial pathways for cancer therapy.

Emerging evidence, supported by clinical responses to immunotherapy and the recapitulation of sensory symptoms in passive transfer models, shows that autoantibodies (AAbs) may drive neuropathic pain. These findings highlight the importance of immune profiling to enhance diagnosis and treatment, and provide molecular insights into broader pain mechanisms in clinical contexts.

Preventing metastasis remains a major challenge in cancer therapy. Effective strategies should combine immune activation with the inhibition of cancer cell migration and invasion. In this Opinion article, we propose a multimodal approach that integrates migrastatic agents with photodynamic therapy (PDT) and intratumoral immunotherapy (ITI). Migrastatics inhibit cell motility and may reduce the risk of tumor cell dissemination. PDT promotes immunogenic cell death and enhances immune recognition while minimizing damage to healthy tissues. ITI delivers immune stimulants directly into tumors to stimulate local immune responses. This therapeutic strategy could suppress cancer cell plasticity, limit metastasis, and activate antitumor immunity, potentially improving outcomes in cancers prone to early invasion. This comprehensive approach is discussed in the context of current clinical practice.

RNA immunotherapy offers a versatile and scalable platform for reprogramming immune responses in cancer and autoimmunity. Advances in linear mRNA, self-amplifying RNA (saRNA), and circular RNA (circRNA) enable the programmable delivery of therapeutic proteins with improved stability, expression, and targeting. In cancer, RNA platforms have shown clinical promise in neoantigen vaccines, cytokine therapies, and chimeric antigen receptor (CAR) immune cell engineering. In autoimmunity, RNA strategies are being developed to induce antigen-specific tolerance, expand regulatory T cells (Tregs), and deliver anti-inflammatory mediators. Structural optimizations and targeted delivery systems further enhance therapeutic efficacy and safety. This review discusses recent clinical progress, mechanistic foundations, and emerging directions for RNA immunotherapy as a broadly applicable platform across cancer and autoimmune disease contexts.