Sphingosine-1 phosphate (S1P) is a lipid metabolite regulating diverse biological processes, including proliferation, differentiation, migration, and apoptosis, highlighting its physiological and therapeutic significance. Current S1P-based therapeutic approaches primarily focus on modulating the downstream signalling via targeting S1P receptors, however, this is challenged by incomplete receptor internalisation. Sphingosine-1-phosphate lyase (SPL) is a highly conserved enzyme that \"gatekeeps\" the final step of S1P degradation. Cognisant of the complex ligand and receptor interaction and dynamic metabolic networks, the selective modulation of SPL activity presents a new opportunity to regulate S1P biosynthesis and reveal its role in various systems. Over the past decade, an evolving effort has been made to identify new molecules that could block SPL activity in vitro or in vivo. This review focuses on summarising the current understanding of the reported SPL inhibitors identified through various screening approaches, discussing their efficacy in diverse model systems and the possible mechanism of action. Whilst effective modulation of S1P levels via inhibiting SPL is feasible, the specificity of those inhibitors remains inconclusive, presenting a clear challenge for future implications. Yet, none of the currently available SPL inhibitors is proven effective in elevating S1P levels within the central nervous system. This review article embraces future research focusing on investigating selective SPL inhibitors with high potency and possibly blood-brain-barrier permeability, which would aid the development of new S1P-based therapeutics for neurological disorders.

Histone deacetylase 6 (HDAC6) belongs to a class of epigenetic targets that have been found to be a key protein in the association between tumors and cardiovascular disease. Recent studies have focused on the crucial role of HDAC6 in regulating cardiovascular diseases such as atherosclerosis, myocardial infarction, myocardial hypertrophy, myocardial fibrosis, hypertension, pulmonary hypertension, and arrhythmia. Here, we review the association between HDAC6 and cardiovascular disease, the research progress of HDAC6 inhibitors in the treatment of cardiovascular disease, and discuss the feasibility of combining HDAC6 inhibitors with other therapeutic agents to treat cardiovascular disease.

Alzheimer\'s disease (AD), first diagnosed over a century ago, remains one of the major healthcare crises around the globe. Currently, there is no cure or effective treatment. The majority of drug development efforts to date have targeted reduction of amyloid-β peptide (Aβ). Drug development through inhibition of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), resulted in promising early clinical studies. However, nearly all small molecule BACE1 inhibitor drugs failed to live up to expectations in later phase clinical trials, due to toxicity and efficacy issues. This commentary aims to provide a brief review of over two decades of BACE1 inhibitor drug development challenges and efforts for treatment of AD and prospects of future BACE1-based drugs.

Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia, with its prevalence linked to both genetic predisposition and environmental factors. Epigenetic modifications, particularly through histone deacetylases (HDACs), have been recognized for their significant influence on DM pathogenesis. This review focuses on the classification of HDACs, their role in DM and its complications, and the potential therapeutic applications of HDAC inhibitors. HDACs, which modulate gene expression without altering DNA sequences, are categorized into four classes with distinct functions and tissue specificity. HDAC inhibitors (HDACi) have shown efficacy in various diseases, including DM, by targeting these enzymes. The review highlights how HDACs regulate β-cell function, insulin sensitivity, and hepatic gluconeogenesis in DM, as well as their impact on diabetic cardiomyopathy, nephropathy, and retinopathy. Finally, we suggest that targeted histone modification is expected to become a key method for the treatment of diabetes and its complications. The study of HDACi offers insights into new treatment strategies for DM and its associated complications.

Ferroptosis, a regulated form of cell death, is intricately linked to iron‑dependent lipid peroxidation. Recent evidence strongly supports the induction of ferroptosis as a promising strategy for treating cancers resistant to conventional therapies. A key player in ferroptosis regulation is ferroptosis suppressor protein 1 (FSP1), which promotes cancer cell resistance by promoting the production of the antioxidant form of coenzyme Q10. Of note, FSP1 confers resistance to ferroptosis independently of the glutathione (GSH) and glutathione peroxidase‑4 pathway. Therefore, targeting FSP1 to weaken its inhibition of ferroptosis may be a viable strategy for treating refractory cancer. This review aims to clarify the molecular mechanisms underlying ferroptosis, the specific pathway by which FSP1 suppresses ferroptosis and the effect of FSP1 inhibitors on cancer cells.

BACKGROUND: Acquired hemophilia A (AHA) is an autoimmune bleeding disorder caused by neutralizing antibodies against coagulation factor VIII (FVIII). Immunosuppressive therapy (IST) is standard of care to eradicate autoantibody production and protect from further bleeding but carries a risk of severe infection and mortality in frail patients with AHA. Recently, emicizumab has been studied for its potential to reduce the need for early and aggressive IST.
OBJECTIVE: To compare outcomes of two studies that used either IST (GTH-AH 01/2010; n=101) or prophylaxis with emicizumab (GHT-AHA-EMI; n=47) early after diagnosis of AHA.
METHODS: Baseline characteristics were balanced by propensity score matching. Primary endpoint was the rate of clinically relevant new bleeds during the first 12 weeks; secondary endpoints were adverse events and overall survival.
RESULTS: The negative binominal model-based bleeding rate was 68% lower with emicizumab as compared with IST (incident rate ratio 0.325, 95% confidence interval (CI) 0.182-0.581). No difference was apparent in the overall frequency of infections (emicizumab 21%, IST 29%) during the first 12 weeks, but infections were less often fatal in emicizumab treated patients (0%) compared with IST treated patients (11%). Thromboembolic events occurred less often with emicizumab (2%) than IST (7%). Overall survival after 24 weeks was better with emicizumab (90% versus 76%, HR 0.44; 95% CI 0.24-0.81).
CONCLUSIONS: Using emicizumab instead of IST in the early phase after initial diagnosis of AHA reduced bleeding and fatal infections, and improved overall survival.

Fibrosis can occur in almost all tissues and organs and affects normal physiological function, which may have serious consequences, such as organ failure. However, there are currently no effective, broad-spectrum drugs suitable for clinical application. Revealing the process of fibrosis is an important prerequisite for the development of new therapeutic targets and drugs. Studies have shown that the limiting of myofibroblast activation or the promoting of their elimination can ameliorate fibrosis. However, it has not been reported whether a direct decrease in cell contraction can inhibit fibrosis in vivo. Here, we have shown that (-)-blebbistatin (Ble), a non-muscle myosin Ⅱ inhibitor, displayed significant inhibition of liver fibrosis in different chronic injury mouse models in vivo. We found that Ble reduced the stiffness of fibrotic tissues from the early stage, which reduced the extent of myofibroblast activation induced by a stiffer extracellular matrix (ECM). Moreover, Ble also reduced the activation of myofibroblasts induced by TGF-β1, which is the most potent pro-fibrotic cytokine. Mechanistically, Ble reduced mechanical contraction, which inhibited the assembly of stress fibers, decreased the F/G-actin ratio, and led to the exnucleation of YAP1 and MRTF-A. Finally, we verified its broad-spectrum antifibrotic effect in multiple models of organ fibrosis. Our results highlighted the important role of mechanical contraction in myofibroblast activation and maintenance, rather than just a characteristic of activation, suggesting that it may be a potential target to explore broad-spectrum drugs for the treatment of fibrotic diseases.

The SPRY domain-containing SOCS box proteins SPSB1, SPSB2, and SPSB4 utilize their SPRY/B30.2 domain to interact with a short region in the N-terminus of inducible nitric oxide synthase (iNOS), and recruit an E3 ubiquitin ligase complex to polyubiquitinate iNOS, resulting in the proteasomal degradation of iNOS. Inhibitors that can disrupt the endogenous SPSB-iNOS interactions could be used to augment cellular NO production, and may have antimicrobial and anticancer activities. We previously reported the rational design of a cyclic peptide inhibitor, cR8, cyclo(RGDINNNV), which bound to SPSB2 with moderate affinity. We, therefore, sought to develop SPSB inhibitors with higher affinity. Here, we show that cyclic peptides cR7, cyclo(RGDINNN), and cR9, cyclo(RGDINNNVE), have ~6.5-fold and ~2-fold, respectively, higher SPSB2-bindng affinities than cR8. We determined high-resolution crystal structures of the SPSB2-cR7 and SPSB2-cR9 complexes, which enabled a good understanding of the structure-activity relationships for these cyclic peptide inhibitors. Moreover, we show that these cyclic peptides displace full-length iNOS from SPSB2, SPSB1, and SPSB4, and that their inhibitory potencies correlate well with their SPSB2-binding affinities. The strongest inhibition was observed for cR7 against all three iNOS-binding SPSB proteins.

The coronavirus disease 2019 (COVID-19) is caused by a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which spreads rapidly all over the world. The main protease (Mpro) is significant to the replication and transcription of viruses, making it an attractive drug target against coronaviruses. Here, we introduce a series of novel inhibitors which are designed de novo through structure-based drug design approach that have great potential to inhibit SARS-CoV-2 Mproin vitro. High-resolution structures show that these inhibitors form covalent bonds with the catalytic cysteine through the novel dibromomethyl ketone (DBMK) as a reactive warhead. At the same time, the designed phenyl group beside the DBMK warhead inserts into the cleft between H41 and C145 through π-π stacking interaction, splitting the catalytic dyad and disrupting proton transfer. This unique binding model provides novel clues for the cysteine protease inhibitor development of SARS-CoV-2 as well as other pathogens.

Mitochondrial NADH-ubiquinone oxidoreductase (complex I) couples electron transfer from NADH to ubiquinone with proton translocation in its membrane part. Structural studies have identified a long (~ 30 Å), narrow, tunnel-like cavity within the enzyme, through which ubiquinone may access a deep reaction site. Although various inhibitors are considered to block the ubiquinone reduction by occupying the tunnel\'s interior, this view is still debatable. We synthesized a phosphatidylcholine-quinazoline hybrid compound (PC-Qz1), in which a quinazoline-type toxophore was attached to the sn-2 acyl chain to prevent it from entering the tunnel. However, PC-Qz1 inhibited complex I and suppressed photoaffinity labeling by another quinazoline derivative, [125I]AzQ. This study provides further experimental evidence that is difficult to reconcile with the canonical ubiquinone-accessing tunnel model.