Acute kidney injury (AKI) is a major public health concern with significant morbidity and mortality and no current treatments beyond supportive care and dialysis. Preclinical studies have suggested that heme-oxygenase-1 (HO-1), an enzyme that catalyzes the breakdown of heme, has promise as a potential therapeutic target for AKI. Clinical trials involving HO-1 products (biliverdin, carbon monoxide, and iron), however, have not progressed beyond the Phase ½ level. We identified small-molecule inducers of HO-1 that enable us to exploit the full therapeutic potential of HO-1, the combination of its products, and yet-undefined effects of the enzyme system. Through cell-based, high-throughput screens for induction of HO-1 driven by the human HO-1 promoter/enhancer, we identified two novel small molecules and broxaldine (an FDA-approved drug) for further consideration as candidate compounds exhibiting an E_max ≥70% of 5 µM hemin and EC₅₀ <10 µM. RNA sequencing identified shared binding motifs to NRF2, a transcription factor known to regulate antioxidant genes, including HMOX1. In vitro, the cytoprotective function of the candidates was assessed against cisplatin-induced cytotoxicity and apoptosis. In vivo, delivery of a candidate compound induced HO-1 expression in the kidneys of mice. This study serves as the basis for further development of small-molecule HO-1 inducers as preventative or therapeutic interventions for a variety of pathologies, including AKI.

中文翻译：

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血红素加氧酶 1 细胞保护性小分子诱导剂的鉴定


急性肾损伤（AKI）是一个主要的公共卫生问题，发病率和死亡率很高，目前除了支持性护理和透析外没有其他治疗方法。临床前研究表明，血红素加氧酶-1 (HO-1)（一种催化血红素分解的酶）有望成为 AKI 的潜在治疗靶点。然而，涉及 HO-1 产品（胆绿素、一氧化碳和铁）的临床试验尚未超出 1/2 期水平。我们发现了 HO-1 的小分子诱导剂，使我们能够充分利用 HO-1 的治疗潜力、其产品的组合以及酶系统尚未明确的作用。通过基于细胞的高通量筛选，以诱导由人 HO-1 启动子/增强子驱动的 HO-1，我们鉴定了两种新型小分子和溴醛定（FDA 批准的药物），以供进一步考虑作为具有 E 的候选化合物。_最大≥70% 5 µM 氯化血红素和 EC ₅₀ <10 id=29> HMOX1。在体外，针对顺铂诱导的细胞毒性和细胞凋亡评估了候选物的细胞保护功能。在体内，候选化合物的递送诱导小鼠肾脏中 HO-1 的表达。这项研究为进一步开发小分子 HO-1 诱导剂作为预防或治疗干预措施（包括 AKI）奠定了基础。