Lorenzo Arnaboldi

PCSK9 inhibitors represent a cornerstone of lipid-lowering therapy; however, the need for cost containment and simplified routes of administration has stimulated the development of oral small molecules and peptidomimetics capable of modulating or blocking the PCSK9–LDL receptor (LDL-R) interaction, inhibiting PCSK9 mRNA transcription, or preventing lysosomal degradation of the LDL-R. Agents in advanced development include enlicitide (MK-0616) and laroprovstat (AZD0780), while DC371739, NNC0385-0434 (development currently suspended), and CVI-LM001 should also be considered. Enlicitide decanoate, owing to improved intestinal permeability, significantly reduces free PCSK9 (>90%) and LDL-cholesterol (C) (≈60%) in Phase I–II studies, with excellent tolerability. Phase III trials (CORALreef–Lipids and CORALreef–HeFH) have confirmed LDL-C reductions of 55–60%, along with favourable effects on non-HDL-C, apolipoprotein B (apoB), and Lipoprotein(a) Lp(a), comparable to those achieved with monoclonal antibodies. AZD0780 demonstrates dose-dependent reductions in LDL-C (up to 50%) and potential synergism with rosuvastatin, whereas NNC0385-0434—despite documenting significant decreases in LDL-C and Lp(a)—has been discontinued. DC371739 (a dual PCSK9/ANGPTL3 inhibitor) and CVI-LM001 (a transcriptional modulator) may represent additional therapeutic perspectives. Overall, oral PCSK9 inhibitors show consistent efficacy and favourable safety profiles, positioning them as next-generation lipid-lowering therapies, pending cardiovascular outcome data from ongoing studies.

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Obesity is associated with various metabolic disorders, such as insulin resistance and adipose tissue inflammation (ATM), characterized by macrophage infiltration into adipose cells. This study presents a new Drosophila model to investigate the mechanisms underlying these obesity-related pathologies. We employed genetic manipulation to reduce ecdysone levels to prolong the larval stage. These animals are hyperphagic and exhibit features resembling obesity in mammals, including increased lipid storage, adipocyte hypertrophy and high circulating glucose levels. Moreover, we observed significant infiltration of immune cells (hemocytes) into the fat bodies, accompanied by insulin resistance. We found that attenuation of Eiger/TNFα signaling reduced ATM and improved insulin sensitivity. Furthermore, using metformin and the antioxidants anthocyanins, we ameliorated both phenotypes. Our data highlight evolutionarily conserved mechanisms allowing the development of Drosophila models for discovering therapeutic pathways in adipose tissue immune cell infiltration and insulin resistance. Our model can also provide a platform to perform genetic screens or test the efficacy of therapeutic interventions for diseases such as obesity, type 2 diabetes and non-alcoholic fatty liver disease.

Physiologically, smooth muscle cells (SMC) and nitric oxide (NO) produced by endothelial cells strictly cooperate to maintain vasal homeostasis. In atherosclerosis, where this equilibrium is altered, molecules providing exogenous NO and able to inhibit SMC proliferation may represent valuable antiatherosclerotic agents. Searching for dual antiproliferative and NO-donor molecules, we found that furoxans significantly decreased SMC proliferation in vitro, albeit with different potencies. We therefore assessed whether this property is dependent on their thiol-induced ring opening. Indeed, while furazans (analogues unable to release NO) are not effective, furoxans’ inhibitory potency parallels with the electron-attractor capacity of the group in 3 of the ring, making this effect tunable. To demonstrate whether their specific block on G1-S phase could be NO-dependent, we supplemented SMCs with furoxans and inhibitors of GMP- and/or of the polyamine pathway, which regulate NO-induced SMC proliferation, but they failed in preventing the antiproliferative effect. To find the real mechanism of this property, our proteomics studies revealed that eleven cellular proteins (with SUMO1 being central) and networks involved in cell homeostasis/proliferation are modulated by furoxans, probably by interaction with adducts generated after degradation. Altogether, thanks to their dual effect and pharmacological flexibility, furoxans may be evaluated in the future as antiatherosclerotic molecules.

Arrhythmogenic cardiomyopathy (ACM) is hallmarked by ventricular fibro‐adipogenic alterations, contributing to cardiac dysfunctions and arrhythmias. Although genetically determined (e.g., PKP2 mutations), ACM phenotypes are highly variable. More data on phenotype modulators, clinical prognosticators, and etiological therapies are awaited. We hypothesized that oxidized low‐density lipoprotein (oxLDL)‐dependent activation of PPARγ, a recognized effector of ACM adipogenesis, contributes to disease pathogenesis. ACM patients showing high plasma concentration of oxLDL display severe clinical phenotypes in terms of fat infiltration, ventricular dysfunction, and major arrhythmic event risk. In ACM patient‐derived cardiac cells, we demonstrated that oxLDLs are major cofactors of adipogenesis. Mechanistically, the increased lipid accumulation is mediated by oxLDL cell internalization through CD36, ultimately resulting in PPARγ upregulation. By boosting oxLDL in a Pkp2 heterozygous knock‐out mice through high‐fat diet feeding, we confirmed in vivo the oxidized lipid dependency of cardiac adipogenesis and right ventricle systolic impairment, which are counteracted by atorvastatin treatment. The modulatory role of oxidized lipids on ACM adipogenesis, demonstrated at cellular, mouse, and patient levels, represents a novel risk stratification tool and a target for ACM pharmacological strategies.