Heart failure with reduced ejection fraction (HFrEF) remains a significant global health concern, characterized by high rates of morbidity, mortality, and frequent hospitalizations. Despite substantial progress in medical therapies over the past decades, the clinical course of HFrEF is often progressive, necessitating continuous research into novel and refined therapeutic strategies to improve patient outcomes. The management of HFrEF is a dynamic field, with clinical practice guidelines undergoing regular updates to incorporate the latest evidence and emerging treatment approaches. This constant evolution underscores the importance of ongoing investigation and the need for healthcare professionals to remain informed about the newest advancements in this area. The research topic "Advanced Therapeutic Strategies and Safety Profiles in Heart Failure with Reduced Ejection Fraction," published in Frontiers in Pharmacology, serves as a valuable platform for the dissemination of cutting-edge research focused on enhancing the treatment and safety profiles for individuals living with HFrEF. This topic encompasses a wide range of investigations, including the application of artificial intelligence and machine learning for predicting therapeutic outcomes, detailed evaluations of drug efficacy and safety across diverse patient populations, comparative studies of different treatment strategies, clinical trials exploring novel pharmacological agents, and the integration of advanced diagnostic tools to personalize treatment responses. This editorial aims to critically analyze and contextualize three specific studies recently published within this research topic, integrating their findings with the current understanding of HFrEF management up to the year 2025.By examining these recent contributions, this editorial seeks to provide an expert perspective on their significance and potential impact on the evolving landscape of HFrEF therapy.The cornerstone of contemporary HFrEF management lies in the implementation of guideline-directed medical therapy (GDMT), which has demonstrably improved survival and reduced hospitalizations (Heidenreich et al., 2022;Carrizales-Sepúlveda et al., 2024;Beghini et al., 2025). This foundational approach is built upon the synergistic effects of four main classes of medications: Angiotensin Receptor-Neprilysin Inhibitors (ARNIs), which are often preferred as first-line renin-angiotensin system inhibitors due to their superior efficacy compared to ACE inhibitors or angiotensin receptor blockers; betablockers, which play a crucial role in mitigating the detrimental effects of the sympathetic nervous system; mineralocorticoid receptor antagonists (MRAs), which help to counteract the effects of aldosterone; and Sodium-Glucose Cotransporter-2 Inhibitors (SGLT2is), which have emerged as a transformative therapy demonstrating significant benefits in reducing heart failure hospitalizations and cardiovascular mortality across a broad range of patients with and without diabetes. Current guidelines increasingly emphasize the importance of initiating and rapidly up-titrating these four foundational therapies to their maximally tolerated doses within the first few months following diagnosis to achieve optimal clinical outcomes. Major guideline updates, such as the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure and the 2023 ESC Focused Update of the 2021 ESC Guidelines, have further refined the recommendations for HFrEF management (Heidenreich et al., 2022). Notably, these updates highlight the expanded role of SGLT2 inhibitors across the entire spectrum of left ventricular ejection fraction, signifying a significant shift in the therapeutic paradigm (Carrizales-Sepúlveda et al., 2024).Beyond these foundational therapies, other emerging strategies and considerations have gained prominence in the management of HFrEF up to 2025 (Beghini et al., 2025).Vericiguat, an oral soluble guanylate cyclase stimulator, is recommended for consideration in patients with worsening HFrEF despite optimal GDMT, based on the findings of the VICTORIA trial (PW et al., 2020). Intravenous iron supplementation is increasingly recognized for its benefits in symptomatic patients with HFrEF and iron deficiency, improving symptoms and quality of life and potentially reducing heart failure hospitalizations (Beghini et al., 2025). Furthermore, the integration of palliative care into the management of advanced heart failure is gaining increasing recognition as a crucial component for improving patient quality of life and addressing their individual goals of care (Carrizales-Sepúlveda et al., 2024). The 2024 ACC Expert Consensus Decision Pathway for Treatment of Heart Failure With Reduced Ejection Fraction further reinforces the central role of the "four pillars" of GDMT, emphasizing the preferred use of ARNIs as the initial renin-angiotensin sy