Mechanistic study of the novel peroxidase mimetic DhHP-6 in metabolic cataracts
Zhuoya Li1, Ping Gong2, Yuxin Tian2
1Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, 130041, Jilin, China.
Abstract:
Metabolic disorders such as diabetes and hypergalactosemia often induce oxidative damage and mitochondrial dysfunction in the lens, leading to metabolic cataracts. Although surgical intervention remains the primary treatment, its associated risks and complications underscore the need for pharmacological alternatives with multifaceted protective effects. Deuterohemin-βAla-His-Thr-Val-Glu-Lys (DhHP-6), a novel enzyme mimic of microperoxidase-11, has demonstrated potent reactive oxygen species (ROS)-scavenging activity in vivo. Our previous studies have confirmed its efficacy in mitigating lens opacity and enhancing antioxidant enzyme levels in galactose-induced cataract models. To further elucidate the underlying mechanisms, we established both in vivo galactose-induced rat models and in vitro lens epithelial cell models. The results revealed that DhHP-6 significantly alleviated lens opacity by activating the NRF2/KEAP1/HO-1 pathway, thereby boosting antioxidant enzyme activity, restoring ATP levels, and inhibiting apoptotic signaling. Crucially, in vitro analyses confirmed DhHP-6's ability to maintain mitochondrial structural integrity and functional homeostasis through this pathway, thereby preventing the initiation of apoptosis cascades. These findings demonstrate that DhHP-6 attenuates metabolic cataract progression through multi-target mechanisms orchestrated by the NRF2/KEAP1/HO-1 pathway, integrating antioxidative defense, mitochondrial homeostasis restoration, and apoptosis inhibition into a unified therapeutic strategy.
Insights
Deuterohemin-βAla-His-Thr-Val-Glu-Lys (DhHP-6) effectively treats metabolic cataracts by activating the NRF2/KEAP1/HO-1 pathway. This novel therapeutic approach reduces lens opacity, enhances antioxidant defenses, and prevents cell death.
Area of Science:
- Biochemistry
- Ophthalmology
- Pharmacology
Background:
- Metabolic disorders like diabetes cause oxidative damage and mitochondrial dysfunction, leading to cataracts.
- Current cataract treatment is primarily surgical, necessitating safer pharmacological alternatives.
- Deuterohemin-βAla-His-Thr-Val-Glu-Lys (DhHP-6), a microperoxidase-11 mimic, shows promise as a ROS scavenger.
Purpose of the Study:
- To investigate the therapeutic mechanisms of DhHP-6 in metabolic cataract models.
- To elucidate the role of the NRF2/KEAP1/HO-1 pathway in DhHP-6's protective effects.
- To evaluate DhHP-6's impact on lens opacity, oxidative stress, mitochondrial function, and apoptosis.
Main Methods:
- Established in vivo galactose-induced rat models and in vitro lens epithelial cell models.
- Assessed lens opacity, antioxidant enzyme activity, ATP levels, and apoptotic markers.
- Utilized molecular pathway analysis to investigate the NRF2/KEAP1/HO-1 signaling cascade.
- Examined mitochondrial structure and function using in vitro cell models.
Main Results:
- DhHP-6 significantly reduced lens opacity in galactose-induced cataract models.
- Activation of the NRF2/KEAP1/HO-1 pathway by DhHP-6 boosted antioxidant enzyme activity and restored ATP levels.
- DhHP-6 inhibited apoptotic signaling and maintained mitochondrial structural integrity and function in vitro.
- These effects were mediated through the NRF2/KEAP1/HO-1 pathway, preventing apoptosis.
Conclusions:
- DhHP-6 demonstrates significant therapeutic potential for metabolic cataracts.
- The NRF2/KEAP1/HO-1 pathway is a key mediator of DhHP-6's protective effects.
- DhHP-6 offers a multi-target strategy for cataract treatment by integrating antioxidant defense, mitochondrial homeostasis, and apoptosis inhibition.
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