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<p>Rhabdomyolysis-induced acute kidney injury (RM-AKI) is mediated primarily by myoglobin (Mb) toxicity, yet effective targeted therapies remain unavailable. Through computational structural modeling, we uncovered that the haptoglobin β-subunit (Hpβ) can bind Mb, forming a structurally stable complex. We then engineered a 55 kDa recombinant GST-Hpβ fusion protein and demonstrated that this engineered construct exhibits robust binding affinity for free Mb (17.8 kDa), thereby generating a stable 72.8 kDa GST-Hpβ-Mb complex. Significantly, this complex surpasses the molecular size threshold of the glomerular filtration barrier (~69 kDa), thereby preventing Mb from being filtered into the renal tubules and inflicting subsequent pathological damage. Further analysis revealed that the GST-Hpβ-Mb complex is expeditiously eliminated via CD163-mediated macrophage phagocytosis. Employing well-established RM-AKI murine models, we demonstrated that a single intraperitoneal administration of the GST-Hpβ fusion protein markedly improves survival, ameliorates renal function, and alleviates kidney damage, with protective effects lasting beyond a two-week period. In sum, the GST-Hpβ fusion protein offers a novel and promising biotherapeutic agent that addresses the fundamental pathophysiology of RM-AKI.</p>

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Engineered haptoglobin β fusion protein targets myoglobin and ameliorates rhabdomyolysis-associated acute kidney injury

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月25日

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  • Ning Li,
  • Yuru Wang,
  • Lu Han,
  • Ou Qiao,
  • Xinyue Wang,
  • Herui Hao,
  • Xin Chen,
  • Pengtao Wang,
  • Sania Saeed,
  • Jing Wang,
  • Fengjiao Bao,
  • Yingjie Hou,
  • Li Zhang,
  • Xiaohong Duan,
  • Shuquan Rao,
  • Yanhua Gong

摘要

Rhabdomyolysis-induced acute kidney injury (RM-AKI) is mediated primarily by myoglobin (Mb) toxicity, yet effective targeted therapies remain unavailable. Through computational structural modeling, we uncovered that the haptoglobin β-subunit (Hpβ) can bind Mb, forming a structurally stable complex. We then engineered a 55 kDa recombinant GST-Hpβ fusion protein and demonstrated that this engineered construct exhibits robust binding affinity for free Mb (17.8 kDa), thereby generating a stable 72.8 kDa GST-Hpβ-Mb complex. Significantly, this complex surpasses the molecular size threshold of the glomerular filtration barrier (~69 kDa), thereby preventing Mb from being filtered into the renal tubules and inflicting subsequent pathological damage. Further analysis revealed that the GST-Hpβ-Mb complex is expeditiously eliminated via CD163-mediated macrophage phagocytosis. Employing well-established RM-AKI murine models, we demonstrated that a single intraperitoneal administration of the GST-Hpβ fusion protein markedly improves survival, ameliorates renal function, and alleviates kidney damage, with protective effects lasting beyond a two-week period. In sum, the GST-Hpβ fusion protein offers a novel and promising biotherapeutic agent that addresses the fundamental pathophysiology of RM-AKI.