eng Oriental Scientific Publishing Company Biomedical and Pharmacology Journal 0974-6242 2025-09-19 18 October Spl Edition 67568 article Jayasri Bantaram 1 Shakthi Harikrishnan 1 Sandhya Ravishankar 1 Renukadevi Jeyavelkumaran 1 Department of Pharmaceutics, Saveetha College of Pharmacy, Saveetha Institute of Medical and Technical Sciences, Chennai, India. Parkinson’s disease (PD) is a progressive neurodegenerative illness characterized by the buildup of misfolded alpha-synuclein in Lewy bodies and the loss of dopaminergic neurons in the substantia nigra.  The unfolded protein response (UPR) and endoplasmic reticulum (ER) stress have been implicated in the pathophysiology of Parkinson’s disease (PD) in recent research.BiP/GRP78, an ER-resident chaperone, serves as a central regulator of the UPR by sensing misfolded proteins and modulating three primary stress sensors: PERK, IRE1, and ATF6. While BiP initially acts protectively by restoring ER homeostasis, its sustained activation may lead to maladaptive UPR signaling and neuronal apoptosis. Experimental models have demonstrated that agents such as salubrinal can modulate BiP levels and UPR activity, offering neuroprotection. Moreover, small molecules targeting BiP interactions or its ATPase activity are emerging as potential therapeutics. However, challenges such as blood–brain barrier penetration, tissue-specific effects, and long-term safety must be addressed. Future strategies may include targeted delivery systems, combination therapies involving autophagy modulation, and personalized treatment guided by BiP expression or genomic profiling. This review outlines the dual role of BiP in PD and discusses its therapeutic implications, highlighting the need for precise modulation to maximize clinical benefits while minimizing risks. https://biomedpharmajournal.org/vol18octoberspledition/bip-grp78-and-unfolded-protein-response-in-parkinsons-disease-mechanisms-therapeutic-potential-and-future-directions/ Alpha-synuclein Apoptosis BiP (Binding Immunoglobulin Protein) Endoplasmic reticulum  stress Protein aggregation Unfolded protein response