## 10 Therapeutic Perspectives  
Elevated RIPK1 activity is associated with numerous human diseases, making it a crucial target for therapeutic interventions. In theory, RIPK1 kinase inhibitors will prevent RIPK1 hyperactivation-induced inflammatory diseases, while preserving RIPK1 scaffold function to maintain its basal inhibition on RIPK3, ZBP1, and FADD/Caspase-8, thus averting unwanted necroptosis or apoptosis. Indeed, in mouse models, RIPK1 inhibitors have been shown to prevent or alleviate clinical symptoms of various diseases, including SIRS, ischemia-induced tissue injury, neurodegeneration, and bacterial and viral infections [2]. Currently, numerous RIPK1 inhibitors are in different phases of clinical trials for a spectrum of human inflammatory diseases, ranging from rheumatoid arthritis, cutaneous lupus erythematosus, ulcerative colitis, SARS-CoV-2 infection, to Alzheimer's disease and ALS (Table 1) [125; 126; 127; 128; 129; 130; 131] (ClinicalTrials.gov). Many of these RIPK1 inhibitors have successfully passed phase I safety tests, revealing important dose-dependent effects. For example, the brain-penetrant RIPK1 inhibitor, DNL104, demonstrated a clear dose-response relationship in its safety profile. In the single-ascending-dose group, DNL104 was well tolerated across a range of doses, indicating a favorable safety profile at lower concentrations. However, in the multiple-ascending-dose group, 37.5% of subjects experienced post-dose liver toxicity, highlighting the potential for adverse effects at higher cumulative doses or with prolonged exposure [125]. This dose-dependent toxicity underscores the importance of careful dose optimization in RIPK1 inhibitor development. Some inhibitors have progressed to phase II trials, where dose-ranging studies are further refining the therapeutic window and optimal dosing regimens. However, as yet, no RIPK1 inhibitors have advanced to phase III trials, partly due to the ongoing process of establishing the most effective and safe dosing strategies for long-term treatment. Considering the diverse functions of RIPK1 and the uncertain outcomes of the clinical trials involving RIPK1 inhibitors, there is a pressing need to identify novel targets for specifically inhibiting its cell-death-promoting activity. Due to the pivotal role of PPP1R3G/PP1\(\gamma\) in removing inhibitory phosphorylation sites on RIPK1, it emerges as a promising alternative therapeutic target. Notably, PPP1R3G interacts with PP1\(\gamma\) through a short RVQF motif, presenting a unique opportunity to develop short-peptide mimetics that disrupt PPP1R3G and PP1\(\gamma\) interaction. This disruption could potentially block RIPK1-dependent apoptosis and necroptosis. The same approach has been successfully employed in designing the Smac-mimetics, which mimics the four-residue AVPI sequence in the SMAC protein. These mimetics specifically mimic the interaction between SMAC and IAPs to induce IAP degradation, thereby activating apoptosis [27; 28; 132]. Unlike RIPK1 inhibitors, these inhibitors of PPP1R3G/PP1\(\gamma\) maintain the inhibitory phosphorylation sites on RIPK1, preventing its hyperactivation, while not altering RIPK1 scaffold function, thereby preserving its other functions. At the same time, these inhibitors would have minimal impact on the phosphatase activity of PP1\(\gamma\), thus maintaining its other vital functions. This innovative approach holds potential for therapeutic interventions targeting inflammatory diseases associated with heightened RIPK1 activity, while minimizing any adverse effects on cellular homeostasis.