PARP16 is an endoplasmic reticulum-resident mono-ADP-ribosyltransferase that regulates protein homeostasis through multiple cellular processes. Functionally, PARP16 catalyzes mono-ADP-ribosylation (MARylation) of ribosomal proteins including RPL14, RPL24, and RPS6, inhibiting polysome assembly and mRNA translation 1. This activity, promoted by NMNAT2-mediated NAD+ synthesis, maintains proteostasis in cancer cells by preventing toxic protein aggregation 1. PARP16 also activates the unfolded protein response (UPR) by ADP-ribosylating and activating UPR effectors EIF2AK3 (PERK) and ERN1 (IRE1α) 2. Mechanistically, PARP16 functions through the Smyd3-PARP16 epigenetic axis, where histone methyltransferase SMYD3 upregulates PARP16 expression to promote UPR activation 34. Clinically, PARP16 dysfunction is implicated in multiple pathologies: its inhibition reduces ovarian cancer growth 1, PARP16 knockdown alleviates cerebral ischemia/reperfusion injury 5, and PARP16 deletion attenuates cardiac hypertrophy and neointimal hyperplasia 64. Recent drug development has yielded selective PARP16 inhibitors like DB008, enabling mechanistic studies and potential therapeutic applications 7.