Steady progress over four decades toward understanding the pathogenesis and clinical consequences of hepatic fibrosis has led to the expectation of effective antifibrotic drugs, yet none has been approved. Thus, an assessment of the field is timely, to clarify priorities and accelerate progress. Here, we highlight the successes to date but, more importantly, identify gaps and unmet needs, both experimentally and clinically. These include the need to better define cell–cell interactions and etiology-specific elements of fibrogenesis and their link to disease-specific drivers of portal hypertension. Success in treating viral hepatitis has revealed the remarkable capacity of the liver to degrade scar in reversing fibrosis, yet we know little of the mechanisms underlying this response. Thus, there is an exigent need to clarify the cellular and molecular mechanisms of fibrosis regression in order for therapeutics to mimic the liver’s endogenous capacity. Better refined and more predictive in vitro and animal models will hasten drug development. From a clinical perspective, current diagnostics are improving but not always biologically plausible or sufficiently accurate to supplant biopsy. More urgently, digital pathology methods that leverage machine learning and artificial intelligence must be validated in order to capture more prognostic information from liver biopsies and better quantify the response to therapies. For more refined treatment of NASH, orthogonal approaches that integrate genetic, clinical, and pathological data sets may yield treatments for specific subphenotypes of the disease. Collectively, these and other advances will strengthen and streamline clinical trials and better link histologic responses to clinical outcomes.

中文翻译：

---

肝纤维化 2022：未满足的需求和未来蓝图

四十多年来，在了解肝纤维化的发病机制和临床后果方面取得了稳步进展，人们期待有效的抗纤维化药物，但尚未获得批准。因此，对该领域的评估是及时的，以明确优先事项并加快进展。在这里，我们重点介绍迄今为止取得的成功，但更重要的是，找出实验和临床方面的差距和未满足的需求。其中包括需要更好地定义细胞间相互作用和纤维发生的病因特异性因素，以及它们与门脉高压的疾病特异性驱动因素的联系。治疗病毒性肝炎的成功揭示了肝脏在逆转纤维化过程中降解疤痕的非凡能力，但我们对这种反应的潜在机制知之甚少。因此，迫切需要阐明纤维化消退的细胞和分子机制，以便治疗模拟肝脏的内源性能力。更精细和更具预测性的体外和动物模型将加速药物开发。从临床角度来看，目前的诊断方法正在改进，但并不总是在生物学上合理或足够准确以取代活检。更紧迫的是，必须验证利用机器学习和人工智能的数字病理学方法，以便从肝脏活检中获取更多的预后信息并更好地量化对治疗的反应。为了更精细地治疗 NASH，整合遗传、临床和病理数据集的正交方法可能会产生针对该疾病特定亚表型的治疗方法。总的来说，