Despite major advances in lipid-lowering therapy and the widespread implementation of statins, ezetimibe, and PCSK9-targeted interventions, cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide. Intensive lowering of low-density lipoprotein cholesterol (LDL-C) has substantially reduced cardiovascular events; however, a considerable degree of residual cardiovascular risk persists even among patients achieving very low LDL-C levels. This observation has shifted contemporary cardiovascular research toward a broader understanding of atherosclerosis as a multifactorial disorder involving triglyceride-rich lipoproteins (TRLs), apolipoprotein B (APOB)-containing particles, dysfunctional high-density lipoproteins (HDLs), lipoprotein(a) [Lp(a)], endothelial dysfunction, and chronic vascular inflammation. Emerging evidence further suggests that psychological and behavioral factors, including specific personality traits and chronic psychosocial stress, may contribute independently to cardiovascular disease susceptibility and outcomes. The present review summarizes emerging risk factors associated with residual cardiovascular risk and highlights novel therapeutic strategies beyond LDL-C lowering. Collectively, current evidence supports a transition from a simplistic LDL-C-centric paradigm toward a multiple risk factor approach for atherosclerosis prevention and treatment.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively triggers apoptosis in malignant, infected, or stressed cells while sparing normal tissues, making it an attractive therapeutic candidate. However, many tumors exhibit intrinsic or acquired resistance to TRAIL, driven by reduced DR4/DR5 surface expression, elevated decoy receptor levels, dysregulated DISC assembly, overexpression of c-FLIP and anti-apoptotic Bcl-2 family proteins, or activation of survival pathways such as NF-κB, PI3K/Akt, and MAPK. Moreover, TRAIL receptors can initiate non-canonical signaling pathways that promote migration, invasion, and metastasis in specific oncogenic contexts, thereby further limiting therapeutic efficacy. We aimed to integrate mechanistic insights into TRAIL biology with current therapeutic advances, providing a comprehensive framework for understanding resistance and for designing rational TRAIL-based combination strategies. We summarized the structural and signaling features of TRAIL receptors, outlined the major determinants of TRAIL sensitivity, and evaluated predictive biomarkers that may guide patient selection. In addition, we examined next-generation TRAIL agonists and targeted delivery systems developed to enhance receptor clustering, pharmacokinetics, and tumor specificity. Together, these insights highlight the therapeutic promise of mechanistically informed TRAIL combinations. A deeper understanding of resistance pathways and biomarker-guided stratification will be essential for restoring apoptotic competence and improving clinical outcomes.