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Background <p>Alzheimer’s disease (AD) is the most common neurodegenerative dementia, with its primary symptoms appearing only after substantial neuronal death. Streptozotocin (STZ) is a neurotoxic compound that induces neurodegenerative effects similar to those seen in AD. AD is a complex and multifactorial disorder, and the exact etiology of neuronal loss remains elusive. In recent years, hyperactivation of mammalian ste-20-like kinase − 1/2 (MST1/2)-mediated Hippo signaling is critical for neuronal death in AD pathophysiology. Our previous research on a rat model of sporadic AD revealed that inhibiting Hippo signaling via the MST1/2 small-molecule antagonist Xmu-mp-1 is a promising therapeutic strategy for AD. Based on these findings, the present study aimed to investigate the therapeutic potential of Xmu-mp-1 in mitigating STZ-induced neurotoxicity using differentiated SH-SY5Y cells.</p> Methods and results <p>In this study, differentiated SH-SY5Y cells were pretreated with 1 µM Xmu-mp-1 for 2&#xa0;h, prior to 2 mM STZ exposure for 24&#xa0;h. We assessed the effects on cytotoxicity, oxidative stress, mitochondrial dysfunction, and apoptosis, followed by an investigation into the underlying mechanistic basis. Our findings revealed that Xmu-mp-1 pretreatment considerably attenuated toxicity and improved cell survival in STZ-exposed SH-SY5Y cells by attenuating STZ-induced intracellular oxidative stress, mitochondrial depolarization, neuronal apoptosis, and neurodegeneration. Xmu-mp-1 apparently involved modulation of Hippo signaling to mediate these neuroprotective effects.</p> Conclusions <p>Taken together, these findings suggest that MST1-mediated neuronal apoptosis may contribute to neuronal death in STZ-induced neurotoxicity, and inhibiting MST/Hippo signaling via Xmu-mp-1 could represent an effective approach to alleviate AD-associated neurotoxic events.</p>

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Xmu-mp-1 attenuates streptozotocin-induced neurotoxicity in SH-SY5Y cells: potential role of Hippo pathway modulation

  • 期刊论文

  • 发表日期：

    2026年2月13日

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  • Manas Ranjan Sahu,
  • Mir Hilal Ahmad,
  • Amal Chandra Mondal

摘要

Background

Alzheimer’s disease (AD) is the most common neurodegenerative dementia, with its primary symptoms appearing only after substantial neuronal death. Streptozotocin (STZ) is a neurotoxic compound that induces neurodegenerative effects similar to those seen in AD. AD is a complex and multifactorial disorder, and the exact etiology of neuronal loss remains elusive. In recent years, hyperactivation of mammalian ste-20-like kinase − 1/2 (MST1/2)-mediated Hippo signaling is critical for neuronal death in AD pathophysiology. Our previous research on a rat model of sporadic AD revealed that inhibiting Hippo signaling via the MST1/2 small-molecule antagonist Xmu-mp-1 is a promising therapeutic strategy for AD. Based on these findings, the present study aimed to investigate the therapeutic potential of Xmu-mp-1 in mitigating STZ-induced neurotoxicity using differentiated SH-SY5Y cells.

Methods and results

In this study, differentiated SH-SY5Y cells were pretreated with 1 µM Xmu-mp-1 for 2 h, prior to 2 mM STZ exposure for 24 h. We assessed the effects on cytotoxicity, oxidative stress, mitochondrial dysfunction, and apoptosis, followed by an investigation into the underlying mechanistic basis. Our findings revealed that Xmu-mp-1 pretreatment considerably attenuated toxicity and improved cell survival in STZ-exposed SH-SY5Y cells by attenuating STZ-induced intracellular oxidative stress, mitochondrial depolarization, neuronal apoptosis, and neurodegeneration. Xmu-mp-1 apparently involved modulation of Hippo signaling to mediate these neuroprotective effects.

Conclusions

Taken together, these findings suggest that MST1-mediated neuronal apoptosis may contribute to neuronal death in STZ-induced neurotoxicity, and inhibiting MST/Hippo signaling via Xmu-mp-1 could represent an effective approach to alleviate AD-associated neurotoxic events.