Pomegranate compound breaks down harmful protein clumps linked to rare heart and nerve disease in early tests

Researchers at Kumamoto University have identified a natural molecule drawn from pomegranate leaves and branches that directly breaks down transthyretin amyloid fibrils in laboratory and animal models which could therefore open a route to therapies that remove established deposits in transthyretin amyloidosis

A research team at Kumamoto University, Kyushu, Japan, has reported that a natural compound isolated from pomegranate leaves and branches can directly dismantle harmful protein aggregates linked to transthyretin amyloidosis – a progressive and potentially life-threatening disorder that affects peripheral nerves and cardiac tissue. The findings have highlighted a potential therapeutic strategy that differs fundamentally from existing approaches.

Transthyretin amyloidosis arises when the transport protein transthyretin, which normally circulates in blood to carry thyroxine and retinol-binding protein, undergoes misfold and accumulates as insoluble amyloid fibrils within tissue. These fibrils deposit in organs such as the heart and across the peripheral nerve system where they disrupt normal structure and function.

Current treatments have focused largely on two strategies:

• to stabilise the native transthyretin tetramer in order to prevent misfolding
• to reduce hepatic production of the protein through gene-silencing approaches.

Although these interventions have improved outcomes, they have shown limited ability to remove amyloid deposits once these structures have formed.

To address this unmet clinical need, the investigators undertook a systematic screen of 1,509 plant extracts drawn from a natural product library. Extracts derived from pomegranate – Punica granatum – leaves and branches exhibited particularly strong activity against pre-formed transthyretin amyloid fibrils. Subsequent chemical fractionation and structural analysis identified 1,2,3,4,6-penta-O-galloyl-β-D-glucose (PGG) as the active component responsible for this effect.

In vitro experiments demonstrated that PGG could disassemble amyloid fibrils formed from both mutant and wild-type transthyretin. This distinction is clinically important, as hereditary forms of transthyretin amyloidosis arise from specific gene mutations, whereas wild-type transthyretin can also form deposits in older individuals, particularly within the heart. Under identical experimental conditions, PGG selectively disrupted transthyretin aggregates while leaving amyloid-β fibrils – which associate with Alzheimer’s disease – intact. This selective action suggested a degree of molecular specificity, rather than a broad and indiscriminate effect on protein aggregates.

The team extended their work to an in vivo model by use of the nematode Caenorhabditis elegans which expressed fragments of human transthyretin prone to aggregation. Treatment with PGG reduced visible protein deposits within the organism and significantly extended both lifespan and health span compared with untreated controls. These results indicated that fibril disruption translated into measurable physiological benefit in a whole-animal system.

To strengthen the relevance to human disease, the researchers also examined amyloid fibrils isolated from the cardiac tissue of a patient with hereditary transthyretin amyloidosis. PGG successfully disrupted these patient-derived fibrils in laboratory assays. This observation provided direct evidence that the compound can act on authentic human amyloid material, rather than solely on synthetic preparations.

Structural studies further clarified the basis of activity. PGG consists of a glucose core substituted with multiple galloyl groups. The analyses indicated that the presence and arrangement of these galloyl moieties proved essential for amyloid-disrupting activity. These chemical features appear to facilitate interaction with the ordered β-sheet architecture that characterises amyloid fibrils, thereby destabilising their structure. This insight offers a rational foundation for future medicinal chemistry efforts to refine potency and selectivity.

Although the work remains at a preclinical stage, the findings have underscored the therapeutic potential of plant-derived small molecules to remove established amyloid deposits. If subsequent studies confirm safety and efficacy in mammalian models and, ultimately, in human subjects, compounds based on PGG could form the basis of a novel class of treatments that do not merely halt further fibril formation but actively dismantle pathogenic aggregates.

For further reading please visit: 10.1016/j.isci.2025.114170