Leukotrienes are potent inflammatory lipid mediators produced primarily by immune cells. Inflammation, being the center stone of two major disease conditions, namely, asthma and inflammatory bowel disease (IBD), has led researchers to study the role of leukotrienes (LTs) in both these disease settings extensively. Several studies indicate a crucial role for LTs in the development and progression of IBD, whereas LTs, especially cysteinyl leukotrienes (cys‐LTs), have been identified as the major contributors to asthma initiation and progression for over three decades. Additionally, the lungs and the gut share several common characteristics, including their exposure to the external environment, similar microbiome composition, and inflammatory responses. These similarities suggest a bidirectional relationship, supported by the increased risk of IBD in asthma patients and vice versa. However, the specific role of LTs in this lung–gut connection remains unclear. This review will examine how several common factors, such as physiology, microbiome, environment, and inflammatory mediators, especially LTs, modulate this crosstalk. The review also highlights in detail how altered leukotriene biosynthesis and signaling contribute to the pathogenesis of both asthma and IBD. Furthermore, we will consider the therapeutic implications of targeting leukotriene pathways for patients with concurrent asthma and IBD in the hope of developing more efficient treatment outcomes for these interconnected conditions. Finally, this review will very briefly explore the involvement of neuronal connections in mediating the lung–gut crosstalk.

Prostaglandin E ₂ (PGE ₂ ) has been implicated in counteracting fibroblast differentiation by TGFβ1 during pulmonary fibrosis. However, the precise mechanism is not well understood. We show here that PGE ₂ via EP ₂ R and EP ₄ R inhibits the expression of mechanosensory molecules Lysyl Oxidase Like 2 (LOXL2), myocardin‐related transcription factor A (MRTF‐A), ECM proteins, plasminogen activation inhibitor 1 (PAI‐1), fibronectin (FN), α‐smooth muscle actin (α‐SMA), and redox sensor (nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4)) required for TGFβ1‐mediated fibroblast differentiation. We further demonstrate that PGE ₂ inhibits fibrotic signaling via Yes‐associated protein (YAP) but does so independently from its actions on SMAD phosphorylation and conserved cylindromatosis (CYLD; deubiquitinase) expression. Mechanistically, PGE ₂ phosphorylates/inactivates YAP downstream of EP ₂ R/Gαs and restrains its translocation to the nucleus, thus inhibiting its interaction with TEA domain family members (TEADs) and transcription of fibrotic genes. Importantly, pharmacological or siRNA‐mediated inhibition of YAP significantly downregulates TGFβ1‐mediated fibrotic gene expression and myofibroblast formation. Notably, YAP expression is upregulated in the lungs of D. farinae ‐treated wild type (WT) mice relative to saline‐treated WT mice. Our results unravel a unique role for PGE ₂ ‐YAP interactions in fibroblast differentiation, and that PGE ₂ /YAP inhibition can be used as a novel therapeutic target in the treatment of pathological conditions associated with myofibroblasts like asthma.

Cutaneous melanoma remains the most lethal skin cancer due to profound tumor heterogeneity and the frequent development of resistance to current therapies. Here, we identify the cysteinyl leukotriene receptor 1 (CysLT ₁ R) as a previously unrecognized driver of melanoma progression. Analysis of bulk RNA-sequencing datasets from The Cancer Genome Atlas (TCGA) revealed significantly elevated CysLT ₁ R transcript in metastatic tumors compared to primary tumors. Functional studies in murine and human melanoma cells demonstrated that leukotriene D ₄ (LTD ₄ )-mediated activation of CysLT ₁ R promotes melanoma cell proliferation and invasion through the parallel engagement of YAP and ERK signaling pathways. Notably, melanoma cells express LTC ₄ synthase and secrete cysteinyl leukotrienes, establishing a constitutive autocrine signaling loop that sustains CysLT ₁ R activity independently of the host niche. Genetic ablation or pharmacological inhibition of CysLT ₁ R with MK571 significantly attenuated tumor growth in vivo and was associated with inhibition of the YAP-LOXL-2 signaling axis. In addition, studies using Cysltr1 ^–/– mice reveal that host-derived CysLT ₁ R signaling within the tumor microenvironment also contributes to melanoma progression. Together, these findings uncover a previously unrecognized pro-tumorigenic CysLT ₁ R-ERK/YAP,LOXL-2 signaling circuit that promotes cutaneous melanoma progression and highlight CysLT ₁ R as a potential therapeutic target for melanoma.