Disner Geonildo Rodrigo, Wincent Emma, Lima Carla, Lopes-Ferreira Monica
Plataforma Zebrafish of the Laboratory of Applied Toxinology (CeTICS/FAPESP), Butantan Institute, São Paulo 05503-900, Brazil.
Unit of Systems Toxicology, Institute of Environmental Medicine, Karolinska Institutet, 171 77 Solna, Sweden.
Pharmaceuticals (Basel). 2025 Aug 1;18(8):1146. doi: 10.3390/ph18081146.
The candidate therapeutic peptide TnP demonstrates broad, system-level regulatory capacity, revealed through integrated network analysis from transcriptomic data in zebrafish. Our study primarily identifies TnP as a multifaceted modulator of drug metabolism, wound healing, proteolytic activity, and pigmentation pathways. Transcriptomic profiling of TnP-treated larvae following tail fin amputation revealed 558 differentially expressed genes (DEGs), categorized into four functional networks: (1) drug-metabolizing enzymes (, ) and transporters (SLC/ABC families), where TnP alters xenobiotic processing through Phase I/II modulation; (2) cellular trafficking and immune regulation, with upregulated myosin genes (/) enhancing wound repair and - signaling fine-tuning inflammation; (3) proteolytic cascades (, ) coupled to autophagy (, ) and metabolic rewiring (- axis); and (4) melanogenesis-circadian networks (/-) linked to ubiquitin-mediated protein turnover. Key findings highlight TnP's unique coordination of rapid (protease activation) and sustained (metabolic adaptation) responses, enabled by short network path lengths (1.6-2.1 edges). Hub genes, such as (), , and , mediate crosstalk between these systems, while potential risks-including muscle hypercontractility ( overexpression) or cardiovascular effects (-)-underscore the need for targeted delivery. The zebrafish model validated TnP-conserved mechanisms with human relevance, particularly in drug metabolism and tissue repair. TnP's ability to synchronize extracellular matrix remodeling, immune resolution, and metabolic homeostasis supports its development for the treatment of fibrosis, metabolic disorders, and inflammatory conditions. Future work should focus on optimizing tissue-specific delivery and assessing genetic variability to advance clinical translation. This system-level analysis positions TnP as a model example for next-generation multi-pathway therapeutics.
候选治疗性肽TnP通过对斑马鱼转录组数据的综合网络分析，展现出广泛的系统水平调节能力。我们的研究主要确定TnP是药物代谢、伤口愈合、蛋白水解活性和色素沉着途径的多面调节因子。对TnP处理的幼虫进行尾鳍截肢后的转录组分析揭示了558个差异表达基因（DEG），分为四个功能网络：（1）药物代谢酶（，）和转运蛋白（SLC/ABC家族），其中TnP通过I/II期调节改变外源性物质的处理；（2）细胞运输和免疫调节，肌球蛋白基因（/）上调增强伤口修复， - 信号微调炎症；（3）与自噬（，）和代谢重塑（-轴）相关的蛋白水解级联反应（，）；（4）与泛素介导的蛋白质周转相关的黑色素生成 - 昼夜节律网络（/-）。关键发现突出了TnP通过短网络路径长度（1.6 - 2.1条边）实现的快速（蛋白酶激活）和持续（代谢适应）反应的独特协调。枢纽基因，如（）、和，介导这些系统之间的串扰，而潜在风险 - 包括肌肉过度收缩（过表达）或心血管影响（-） - 强调了靶向递送的必要性。斑马鱼模型验证了TnP与人相关的保守机制，特别是在药物代谢和组织修复方面。TnP同步细胞外基质重塑、免疫消退和代谢稳态的能力支持其用于治疗纤维化、代谢紊乱和炎症性疾病的开发。未来的工作应专注于优化组织特异性递送并评估基因变异性以推进临床转化。这种系统水平分析将TnP定位为下一代多途径治疗的典范。
