Decoding the Crosstalk Between Heat Shock Proteins and Phytochemicals in Thyroid Nodule Regression: Mechanisms and Therapeutic Implications.

Thyroid nodules represent one of the most prevalent endocrine disorders, affecting up to 60% of adults worldwide, with diverse biological behaviors ranging from benign hyperplastic nodules to malignant thyroid carcinoma. Heat shock proteins (HSPs), especially HSP70 and HSP90, act as key molecular chaperones involved in cellular proliferation, stress tolerance, and survival, thereby contributing to both benign nodule persistence and malignant transformation. In parallel, phytochemicals such as curcumin, epigallocatechin gallate (EGCG), resveratrol, and quercetin have emerged as bioactive modulators capable of influencing HSP expression and activity. This review decodes the molecular crosstalk between HSPs and phytochemicals, elucidating how these natural compounds regulate signaling cascades including NF-κB, MAPK, and PI3K/Akt to mediate apoptosis, autophagy, and oxidative stress balance. Particular emphasis is placed on differentiating their therapeutic implications for benign nodule regression versus thyroid cancer inhibition. Preclinical evidence demonstrates that phytochemicals can downregulate HSPs, enhance apoptotic signaling, and sensitize tumor cells to therapy; however, clinical translation remains limited due to low bioavailability, off-target effects, and dosage optimization challenges. Addressing these pharmacokinetic and delivery barriers-through nanotechnology and precision-medicine-based approaches-may unlock new integrative strategies for thyroid disease management. Collectively, this review provides a mechanistic and translational framework highlighting HSP-phytochemical interactions as potential molecular targets for improving therapeutic outcomes in both benign and malignant thyroid pathologies.