Background: Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a progressive liver disorder that possesses metabolic dysfunction and shows steatohepatitis. Although the number of patients is globally increasing and many clinical studies have developed medicine for MASLD, most of the studies have failed due to low efficacy. One reason for this failure is the lack of appropriate animal disease models that reflect human MASLD to evaluate the potency of candidate drugs. Methods: We developed a novel choline-deficient and 0.11%-methionine-added high-fat diet (CDAHFD)-based (MASH) diet that can induce murine metabolic-dysfunction-associated steatohepatitis (MASH) without severe body weight loss. We performed kinetic analyses post-feeding and proposed an appropriate timing of MASH pathogenesis by quantitatively analyzing steatosis, inflammation, and fibrosis. Results: This MASH diet induced liver fibrosis earlier than the conventional CDAHFD model. In brief, lipid accumulation, inflammation, and fibrosis started after 1 week from feeding. Lipid accumulation increased until 8 weeks and declined thereafter; on the other hand, liver fibrosis showed continuous progression. Additionally, immune cells, especially myeloid cells, specifically accumulated and induced inflammation in the initiation stage of MASH. Conclusions: The novel MASH diet promotes the dynamics of lipid deposition and fibrosis in the liver, similar to human MASH pathophysiology. Furthermore, immune-cell-derived inflammation possibly contributes to the initiation of MASH pathogenesis. We propose this model can be the new pre-clinical MASH model to discover the drugs against human MASH by evaluating the interaction between parenchymal and non-parenchymal cells.

Pulmonary fibrosis has a poor prognosis due to challenges in early diagnosis and therapeutic intervention. Current treatments remain largely ineffective due to an incomplete understanding of the complex pathology, including the interactions between fibroblasts and profibrotic immune cells within fibrotic lungs. To elucidate the dynamics of fibrosis, we performed single-cell RNA sequencing (scRNA-seq) on bronchoalveolar lavage fluid (BALF) obtained from patients with interstitial lung disease (ILD). We identified the SPP1- and APOE-expressing macrophage population that is commonly present across ILDs. Histological analysis showed that this macrophage population accumulated at the center of fibrotic foci. Furthermore, the ratio of this macrophage population was increased in both progressive pulmonary fibrosis (PPF) and idiopathic pulmonary fibrosis (IPF). Transcriptomic analysis further divided this macrophage population into two subsets: SLC40A1+ or HAMP+ fibrosis-associated macrophages. We found that the relative balance of IL-10 and IL-8 regulated SLC40A1 and HAMP expression within fibrosis-associated macrophages. Additionally, histological analysis revealed that bronchial epithelium expressed IL-8, while type II alveolar epithelial cells expressed IL-10 in the fibrotic lung. SLC40A1+ fibrosis-associated macrophages localized to CD31+ perivascular regions and mediated the uptake and degradation of the hemoglobin–haptoglobin complex. This dual pathway—providing iron via SLC40A1 and intracellular iron accumulation via HAMP—facilitated the transition of fibroblasts into SPP1+ myofibroblasts. Moreover, ferroptotic fibroblasts secreted TGF-β1, which further contributes to fibrotic progression. In conclusion, aberrant iron metabolism orchestrated by fibrosis-associated macrophages may contribute to fibrosis by facilitating the transition of myofibroblasts. These findings provide mechanistic insight into the progression of autonomous pulmonary fibrosis.

The nontuberculous mycobacteria (NTM) isolated from gastric aspirate have demonstrated >85% strain concordance with those from the sputum, suggesting that they originate from the lungs rather than the environment. Gastric aspirate, although not yet internationally recognized, may be a useful supplementary specimen for diagnosing NTM pulmonary disease.

Pulmonary fibrosis is a progressive and life‐threatening lung disorder characterized by excessive fibrogenesis and impaired respiratory function. Nerandomilast, a preferential phosphodiesterase 4B inhibitor, is currently approved for the treatment of idiopathic pulmonary fibrosis and progressive pulmonary fibrosis in several countries following its demonstrated clinical efficacy in Phase III trials. However, its cellular mechanisms of action remain incompletely understood. In this study, we investigated the effects of nerandomilast on a bleomycin‐induced mouse model of lung fibrosis. Nerandomilast treatment attenuates fibrotic remodeling and preserves alveolar epithelial architecture. Single‐cell transcriptomic analyses revealed altered alveolar epithelial cell state dynamics accompanied by increased cell cycle‐associated pathways in alveolar type 2 cells and an increased relative abundance of alveolar type 2 cells. Consistent with the single‐cell findings, nerandomilast was associated with an increased SFTPC‐positive area and the preservation of alveolar epithelial architecture in vivo. Collectively, our findings suggest that nerandomilast attenuates fibrotic remodeling while modulating alveolar epithelial cell state dynamics, which may provide a possible cellular explanation for its clinical efficacy in patients with pulmonary fibrosis.