Keloids are benign fibrotic lesions that frequently cause persistent itch and pain, yet their underlying molecular mechanisms remain poorly defined. Aberrant transforming growth factor-beta (TGF-β) signaling, particularly through noncanonical pathways such as mitogen-activated protein kinase (MAPK), has been implicated in keloid pathogenesis. In this study, we investigated the effects of selective MEK1 inhibition in vitro using NL350-02 on human keloid fibroblasts via bulk RNA sequencing. Treatment with NL350-02 induced substantial transcriptomic reprogramming, including downregulation of TGF-β receptors, IL-6, IL-17 receptors, and proinflammatory chemokines, alongside the upregulation of proapoptotic genes and marked suppression of proliferation (eg, >3000-fold reduction in Ki-67 expression). Pathway analyses revealed significant enrichment in processes related to apoptosis, cytokine signaling, and TGF-β regulation. Despite paradoxical increases in certain collagen transcripts, the concurrent induction of apoptosis suggests an indirect antifibrotic mechanism. Furthermore, transcriptomic overlap with pruritic conditions and the downregulation of itch-related cytokines highlight MEK1 as a potential target for modulating neuroinflammation in keloid-associated itch. These findings suggest that MEK1 inhibition may offer a dual therapeutic benefit, attenuating both fibrosis and pruritus, and warrant further validation in preclinical keloid models.
Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by persistent itching of the skin with its prevalence increasing in the United States. AD has a complex pathogenesis that remains to be fully resolved, though it is shown to involve immune dysregulation and skin barrier dysfunction, with multiple environmental and genetic factors implicated. The interplay between the immune system and environmental exposures can incite immune responses with the release of cytokines, IgE, eosinophils, and mast cells, which trigger symptoms of AD in susceptible patients. There are many therapies used in AD; however, the first-line treatment for flares continues to be corticosteroids. The broad range of therapies available for AD is associated with adverse effects, poor adherence, and financial burden, accentuating the need to assess alternative therapies. A promising alternative therapy is the catechin family, a group of flavonoids with a unique structure that has anti-inflammatory, antimicrobial, antioxidant, and skin barrier modulating properties. In this review, we describe the structure and related properties of catechins, their function, and how they can be utilized in the treatment of AD. Furthermore, we describe limitations associated with the use of catechins and the necessity of further research in this area. The function of catechins has been widely shown to modulate the inflammatory pathway and skin barrier dysfunction that have been implicated in AD and reduce symptoms. While catechins can mitigate symptoms and reduce associated inflammatory markers, further research is required to develop a therapy that retains the beneficial functions of catechins without increasing cytotoxicity.
Chronic kidney disease-associated pruritus (CKD-aP) is a prevalent and challenging symptom in patients with CKD and end-stage renal disease (ESRD). The aim of this review is to update existing evidence on the pathogenesis and treatments of pruritus in CKD and to shed light on areas that hold promise. The uncertain pathogenesis, and thus seemingly miscellaneous causes, identifies chronic itch as an important challenge in health care. A complex interaction of uremic toxin accumulation, micro and systemic inflammation, dysregulation of the opioid system, and mast cell activation may each contribute to the pathophysiology of CKD-aP. No highly satisfactory antipruritic therapeutics are available. Difelikefalin, considered to be a peripherally acting highly selective kappa-opioid receptor agonist, has been shown to have a positive impact on CKD-aP. Approved by the FDA in 2021 for intravenous administration, difelikefalin remains the most recent drug available. A developing area is that altered hemoglobin metabolism may lead to the activation of mas-related G protein-coupled receptors (MRGPRs). As this family of receptors is associated with itch, it is possible that drugs that target certain MRGPRs may be of future benefit in CKD-aP.
Chronic pruritus is a debilitating condition affecting 23-44 million Americans. Recently, kappa opioid agonists (KOAs) have emerged as a novel class of potent antipruritic agents. In 2021, the Food and Drug Administration approved difelikefalin (Korsuva) for the treatment of moderate-to-severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis. Difelikefalin is a potent, peripherally restricted KOA that is intravenously available. Although promising, difelikefalin is currently available as an intravenous composition only, limiting the scope of use. Oral formulations of difelikefalin did not meet the primary endpoint criteria in recent phase 2 clinical trials; however, additional clinical studies are ongoing. The future for KOAs in the treatment of pruritus is encouraging. Orally active pathway-biased KOAs, such as triazole 1.1, may serve as viable alternatives with broader applications. Extended-release compositions, such as the TP-2021 ProNeura subdermal implant, may circumvent the pharmacokinetic issues associated with peptide-based KOAs. Lastly, dual-acting kappa opioid receptor agonist/mu opioid receptor antagonists are orally bioavailable and may be useful in the treatment of various forms of chronic itch. In this review, we summarize the results of KOAs in clinical and preclinical trials and discuss future directions of drug development.
The results indicate that TRPA1 is dispensable for CA-evoked scratching, which depends partly on TRPV1 and TRPV4.
