Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease characterized by extensive extracellular matrix (ECM) deposition by activated myofibroblasts, which are specialized hyper-contractile cells that promote ECM remodeling and matrix stiffening. New insights on therapeutic strategies aimed at reversing fibrosis by targeting myofibroblast fate are showing promise in promoting fibrosis resolution. Previously, we showed that a novel adipocytokine, omentin-1, attenuated bleomycin (BLM)-induced lung fibrosis by reducing the number of myofibroblasts. Apoptosis, deactivation, and reprogramming of myofibroblasts are important processes in the resolution of fibrosis. Here we report that omentin-1 reverses established lung fibrosis by promoting mechanically activated myofibroblasts dedifferentiation into lipofibroblasts. Omentin-1 promotes myofibroblasts lipogenic differentiation by inhibiting dimerization and nuclear translocation of glycolytic enzymes pyruvate kinase isoform M2 (PKM2) and activation of the downstream Yes-associated protein (YAP) by increasing the cofactor fructose-1,6-bisphosphate (F1, 6BP, FBP). Moreover, omentin-1 activates proliferator-activated receptor gamma (PPARγ) signaling, the master regulator of lipogenesis, and promotes the upregulation of the lipogenic differentiation-related protein perilipin 2 (PLIN2) by suppressing the PKM2-YAP pathway. Ultimately, omentin-1 facilitates myofibroblasts transformation into the lipofibroblast phenotype, with reduced collagen synthesis and enhanced degradation properties, which are crucial mechanisms to clear the ECM deposition in fibrotic tissue, leading to fibrosis resolution. Our results indicate that omentin-1 targets mechanical signal accelerates fibrosis resolution and reverses established lung fibrosis by promoting myofibroblasts lipogenic differentiation, which is closely associated with ECM clearance in fibrotic tissue. These findings suggest that targeting mechanical force to promote myofibroblast lipogenic differentiation is a promising therapeutic strategy against persistent lung fibrosis.

特发性肺纤维化 (IPF) 是一种进行性致命性肺部疾病，其特征是活化的肌成纤维细胞导致广泛的细胞外基质 (ECM) 沉积，肌成纤维细胞是一种特殊的过度收缩细胞，可促进 ECM 重塑和基质硬化。通过靶向肌成纤维细胞命运来逆转纤维化的治疗策略的新见解在促进纤维化消退方面显示出希望。此前，我们发现一种新型脂肪细胞因子 omentin-1 通过减少肌成纤维细胞的数量来减轻博来霉素 (BLM) 诱导的肺纤维化。肌成纤维细胞的凋亡、失活和重编程是纤维化消退的重要过程。在这里，我们报告omentin-1通过促进机械激活的肌成纤维细胞去分化为脂肪成纤维细胞来逆转已形成的肺纤维化。 Omentin-1 通过抑制糖酵解酶丙酮酸激酶同工型 M2 (PKM2) 的二聚化和核转位来促进肌成纤维细胞的脂肪分化，并通过增加辅助因子果糖-1,6-二磷酸 (F1, 6BP) 来激活下游 Yes 相关蛋白 (YAP) ，FBP）。此外，omentin-1 激活增殖物激活受体 γ (PPARγ) 信号（脂肪生成的主要调节因子），并通过抑制 PKM2-YAP 通路促进脂肪生成分化相关蛋白 perilipin 2 (PLIN2) 的上调。最终，omentin-1 促进肌成纤维细胞转化为脂肪成纤维细胞表型，减少胶原合成并增强降解特性，这是清除纤维化组织中 ECM 沉积的关键机制，从而消除纤维化。 我们的结果表明，omentin-1 靶向机械信号，通过促进肌成纤维细胞脂肪生成分化来加速纤维化消退并逆转已形成的肺纤维化，这与纤维化组织中 ECM 清除密切相关。这些发现表明，以机械力促进肌成纤维细胞脂肪生成分化是对抗持续性肺纤维化的一种有前途的治疗策略。