High-density lipoprotein: a biomarker and therapeutic target in sepsis

Li et al. Critical Care (2025) 29:453 https://doi.org/10.1186/s13054-025-05702-2 Critical Care Open Access REVIEW High-density lipoprotein: a biomarker and therapeutic target in sepsis Mohan Li1†, Marina Barros-Pinkelnig1,2†, Sesmu M. Arbous3, Christina Christoffersen4, Patrick C. N. Rensen1 and Sander Kooijman1* Abstract Sepsis is a life-threatening condition that stems from a dysregulated host response to an infection, leading to multi-organ dysfunction and death. Sepsis has a remarkably high global burden and accounts for 20% of all deaths worldwide. Nonetheless, possibilities for treatment are limited mainly to early administration of broad-spectrum antibiotics and providing fluid resuscitation. Innovative strategies that target the excessive inflammatory response while supporting the immune system to clear the infection are highly warranted. It is well-established that sepsis significantly impacts lipoprotein metabolism, leading to a substantial decrease in high-density lipoprotein (HDL) as observed in both experimental and clinical studies. Meanwhile, a high HDL level is associated with better sepsis-related prognosis, indicating that strategies aimed at raising HDL could be beneficial in combating sepsis. In this review, we describe changes in lipoprotein metabolism that occur during sepsis, address the various protective functions of HDL based on its endotoxin-neutralizing, anti-bacterial, anti-inflammatory, and anti-oxidative properties, as well as demonstrate modulation of HDL as a potential therapeutic strategy in sepsis. Keywords High-density lipoprotein (HDL), Lipid metabolism, Sepsis, Septic shock † Mohan Li and Marina Barros-Pinkelnig share co-first authorship. *Correspondence: Sander Kooijman Full list of author information is available at the end of the article © The Author(s) 2025. 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To view a copy of this licence, visit http://creati vecommons.org/licenses/by-nc-nd/4.0/. Li et al. Critical Care (2025) 29:453 Page 2 of 15 Graphical abstract Sepsis and septic shock Sepsis is a complicated, life-threatening disorder that arises from a dysregulated host response to an infection. Sepsis can progress into septic shock, with a critical reduction in organ perfusion, leading to acute multiorgan failure and a substantial risk of death [1]. There are an estimated 50 million sepsis cases worldwide annually, resulting in over 10 million sepsis-related deaths, making it responsible for as much as 20% of all fatalities [2]. Sepsis can be caused by various types of infections, with bacterial infections being the most predominant cause. Gram-positive bacteria account for more than 50% of the sepsis cases, while Gram-negative bacteria and fungi are responsible for 40% and 5% of cases, respectively [3]. The remaining minority of cases is explained by viral (e.g., COVID-19) and parasitic infections [3, 4]. Infections resulting in sepsis frequently originate in the lung, kidney, or enter the body via wounds and burns [5, 6]. Challenges in the treatment of sepsis and septic shock Clinical strategies of sepsis are well-defined and outlined in the guideline regarding the management of sepsis and septic shock [7]. Currently, implementation of a ‘1-hour bundle’ is highly recommended, which encompasses key interventions within the first hour of recognizing potential sepsis in a patient with infection [8]. This includes measuring serum lactate levels, obtaining blood cultures, and initiating broad-spectrum antibiotic therapy. Additionally, early hemodynamic stabilization is prioritized through fluid resuscitation, guided by serum lactate levels. In clinics, the priority besides diagnosis of sepsis is to achieve a mean arterial pressure of at least 65 mm Hg with intravenous fluid resuscitation and vasopressors (e.g., epinephrine, norepinephrine) [7]. Li et al. Critical Care (2025) 29:453 As the approaches mentioned above do not address the dysregulated host response in patients with sepsis, additional immune- and anticoagulation-based therapeutic strategies have been proposed. For example, corticosteroids are widely applied in patients with septic shock as they potently suppress immune responses [9, 10]. Corticosteroids increase blood pressure and improve glomerular filtration rate; as such, the guideline of the Surviving Sepsis Campaign suggests intravenous administration of hydrocortisone at a dose of 200 mg/day in adults with septic shock when adequate fluid resuscitation and vasopressor therapy fail in restoring hemodynamic stability [7]. However, corticosteroids should be considered with caution. While suppression of inflammation by hydrocortisone may be effective in controlling excessive inflammation, it will also dampen the immune response towards the underlying infection, allowing further spreading of pathogens [11]. Probably for that reason, in a recent retrospective analysis of 31,749 patients with sepsis, we were unable to identify sub-population(s) ultimately benefiting from hydrocortisone use, and even reported associations between use of hydrocortisone and increased risk of death [12]. The dysregulated host response in sepsis is mainly induced by excessive endotoxemia (e.g., caused by lipopolysaccharide (LPS) from Gram-negative bacteria or lipoteichoic acid (LTA) from Gram-positive bacteria), which results in excessive production of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin-1-beta (IL-1β) and interleukin-6 (IL-6), also known as the ‘cytokine storm’. Notably, severe systemic inflammation resembling sepsis can also arise from non-infectious insults. For instance, cardiopulmonary bypass can induce gut mucosal ischemia, leading to barrier dysfunction and the translocation of microbes or endotoxins, thereby triggering a postperfusion systemic inflammatory response and multiorgan dysfunction [13]. Other non-infectious triggers include major trauma [14], and cytokine release syndrome associated with monoclonal antibody therapies [15]. Interestingly, even in the earliest hours of sepsis, compensat (...truncated)