Protein farnesylation: from molecular mechanisms to therapeutic targeting in cancer, aging, and beyond.

Protein farnesylation, catalyzed by farnesyltransferase (FTase), covalently attaches a 15-carbon farnesyl lipid to cysteine residues within C-terminal CaaX motifs. This modification governs the subcellular localization, protein-protein interactions, and activity of diverse eukaryotic proteins, including Ras GTPases, nuclear lamins, molecular chaperones, and kinetochore components. This review examines FTase enzymology, substrate recognition, and the sequential post-farnesylation processing by RCE1 and ICMT, alongside the expanding farnesylated proteome and its roles in signaling, nuclear integrity, and mitosis. Central to oncogenic Ras function, farnesylation drove the development of FTase inhibitors (FTIs) as anticancer agents; although alternative prenylation of K-Ras and N-Ras limits efficacy in solid tumors, FTIs show clinical activity in hematologic malignancies. The critical importance of farnesylation is highlighted in Hutchinson-Gilford progeria syndrome, where permanently farnesylated progerin disrupts nuclear architecture, and the FTI lonafarnib extends patient survival. Emerging roles-including driving K-Ras liquid-liquid phase separation and contributing to neurodegeneration and pulmonary hypertension-further broaden the pathophysiological relevance of this modification. Targeting farnesylation through dual prenylation inhibitors, PROTACs, and mevalonate pathway modulation offers promising therapeutic strategies across cancer, progeroid syndromes, and age-related diseases.