Transcriptomic impact of IMA-08401, a novel AHR-agonist resembling laquinimod, on rat liver

IMA-08401 (C2) represents a novel AHR agonist and selective AHR modulator (SAHRM) that is structurally similar to laquinimod (LAQ). Although both compounds produce an identical AHR-active metabolite, IMA-06201 (DELAQ) in vivo, C2 generates it to a far greater degree. SAHRMs have been proposed as therapeutic options for autoimmune disorders, including multiple sclerosis. So far, clinical trials on LAQ have not reported any significant toxic outcomes and C2 has shown low toxicity in rats; however, more research is required due to the functional resemblance of these compounds to the highly toxic AHR agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Here, we report transcriptomic profiling of rat liver following acute (single-dose) and sub-acute exposure (repeated dosing for 5 days followed by a 5-day recovery period) to high doses of C2. Exposure to C2 leads to activation of the AHR, as shown by changes in mRNA abundance of the prototypical AHR-response gene Cyp1a1. We identify a heightened response early after exposure (1 day) that drops off considerably by day 10. Acute exposure to C2 produces a significant immune response, with a focus on antiviral and antibacterial responses that highlights the dual effects of AhR agonists as immunomodulators. Sub-acute exposure leads to an increase in oxidative stress in the liver, the consequences of which require further study on sensitive tissues, such as the CNS and immune system which may be compromised in patients with the target autoimmune disorders.IMA-08401（C2）是一种新型芳香烃受体（AHR）激动剂与选择性AHR调节剂（SAHRM），其结构与拉喹莫德（laquinimod，LAQ）相似。尽管二者在体内均可生成完全相同的AHR活性代谢物IMA-06201（DELAQ），但C2产生该代谢物的水平显著更高。选择性AHR调节剂（SAHRM）已被提出作为包括多发性硬化在内的自身免疫性疾病的治疗候选方案。截至目前，针对拉喹莫德的临床试验尚未报道任何显著毒性事件，且C2在大鼠体内也表现出低毒性；但由于这类化合物与毒性极强的2,3,7,8-四氯二苯并二噁英（2,3,7,8-tetrachlorodibenzo-p-dioxin，TCDD）功能相似，仍需开展更多研究。本研究对大鼠肝脏开展了转录组分析，分别在单次急性暴露及亚急性暴露（连续给药5天，随后停药恢复5天）条件下给予高剂量C2。正如典型AHR应答基因Cyp1a1的mRNA丰度变化所证实，C2暴露可激活AHR。我们观察到暴露早期（第1天）出现增强型应答，至第10天时该应答已显著衰减。单次急性C2暴露可诱导显著的免疫应答，其核心聚焦于抗病毒与抗菌免疫通路，这凸显了AHR激动剂作为免疫调节剂的双重功能。亚急性暴露则会引发肝脏氧化应激水平升高，其相关后果需在敏感组织（如中枢神经系统（CNS）与免疫系统）中开展进一步研究——此类组织在目标自身免疫性疾病患者体内可能已存在损伤。