The extracellular matrix (ECM) is present in all tissues and crucial in maintaining normal tissue homeostasis and function. Defects in ECM synthesis and remodeling can lead to various diseases, while overproduction of ECM components can cause severe conditions like organ fibrosis and influence cancer progression and therapy resistance. Collagens are the most abundant core ECM proteins in physiological and pathological conditions and are predominantly synthesized by fibroblasts. Previous efforts to target aberrant collagen synthesis in fibroblasts by inhibiting pro-fibrotic signaling cascades have been ineffective. More recently, metabolic rewiring downstream of pro-fibrotic signaling has emerged as a critical regulator of collagen synthesis in fibroblasts. Here, we propose that targeting the metabolic pathways involved in ECM biomass generation provides a novel avenue for treating conditions characterized by excessive collagen accumulation. This review summarizes the unique metabolic challenges collagen synthesis imposes on fibroblasts and discusses how underlying metabolic networks could be exploited to create therapeutic opportunities in cancer and fibrotic disease. Finally, we provide a perspective on open questions in the field and how conceptual and technical advances will help address them to unlock novel metabolic vulnerabilities of collagen synthesis in fibroblasts and beyond.

中文翻译：

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胶原蛋白合成的代谢控制


细胞外基质（ECM）存在于所有组织中，对于维持正常组织稳态和功能至关重要。 ECM合成和重塑的缺陷可导致各种疾病，而ECM成分的过量产生可导致器官纤维化等严重疾病，并影响癌症进展和治疗耐药性。胶原蛋白是生理和病理条件下最丰富的核心 ECM 蛋白，主要由成纤维细胞合成。之前通过抑制促纤维化信号级联来靶向成纤维细胞中异常胶原蛋白合成的努力是无效的。最近，促纤维化信号下游的代谢重新布线已成为成纤维细胞中胶原蛋白合成的关键调节因子。在这里，我们建议针对 ECM 生物质生成中涉及的代谢途径，为治疗以胶原蛋白过度积累为特征的疾病提供了一条新途径。这篇综述总结了胶原蛋白合成对成纤维细胞带来的独特代谢挑战，并讨论了如何利用潜在的代谢网络来创造癌症和纤维化疾病的治疗机会。最后，我们对该领域的开放性问题提供了一个视角，以及概念和技术进步如何帮助解决这些问题，以解开成纤维细胞及其他细胞中胶原蛋白合成的新代谢脆弱性。