Cardiac inflammation and hypertrophy develop as a pathologic response to an array of insults, such as myocardial infarctions, chronic systemic hypertension, and valvular defects. Due to the high prevalence of such conditions, there is an increasing need to prevent and halt cardiac hypertrophy. Because cardiac damage and subsequent remodeling can lead to arrhythmias, heart failure, and even sudden cardiac death, inhibition of cardiac hypertrophy is key to reducing cardiovascular-related mortality. The immune system is the driving force behind inflammatory reactions. All three pathways of complement system activation—classical, lectin, and alternative—are implicated in developing cardiac damage, inflammation, and hypertrophy due to infectious and non-infectious causes, autoimmune diseases, genetic polymorphisms, and forms of complement dysregulation. Of interest in this review is the role of the complement system, a collection of soluble and membrane-bound proteins that mediate inflammatory processes through interactions with signaling molecules and immune cells. This review comprehensively discusses the roles of these complement pathways in contagious, chronic inflammatory, genetic, and metabolic diseases. An overview of the completed and terminated clinical trials aimed at preventing cardiovascular mortality by targeting various aspects of the complement system and inflammatory reaction is included. Most current treatments for cardiac inflammation and remodeling primarily target the renin–angiotensin–aldosterone system (RAAS), which prevents further remodeling by reducing myocardial workload. However, moving forward, there may be a place for emerging anti-complement therapeutics, which impair the inflammatory response that generates hypertrophy itself.

Originally discovered in the 1890s, the complement system has traditionally been viewed as a “compliment” to the body’s innate and adaptive immune response. However, emerging data have shown that the complement system is a much more complex mechanism within the body involved in regulating inflammation, gene transcription, attraction of macrophages, and many more processes. Sustained complement activation contributes to autoimmunity and chronic inflammation. Pulmonary hypertension is a disease with a poor prognosis and an average life expectancy of 2–3 years that leads to vascular remodeling of the pulmonary arteries; the pulmonary arteries are essential to host homeostasis, as they divert deoxygenated blood from the right ventricle of the heart to the lungs for gas exchange. This review focuses on direct links between the complement system’s involvement in pulmonary hypertension, along with autoimmune conditions, and the reliance on the complement system for vascular remodeling processes of the pulmonary artery. Furthermore, circadian rhythmicity is highlighted as the disrupted homeostatic mechanism in the inflammatory consequences in the vascular remodeling within the pulmonary arteries, which could potentially open new therapeutic cues. The current treatment options for pulmonary hypertension are discussed with clinical trials using complement inhibitors and potential therapeutic targets that impact immune cell functions and complement activation, which could alleviate symptoms and block the progression of the disease. Further research on complement’s involvement in interstitial lung diseases and pulmonary hypertension could prove beneficial for our understanding of these various diseases and potential treatment options to prevent vascular remodeling of the pulmonary arteries.

Rich HE, et al. Immune Netw. 2026 Apr;26(2):e4. https://doi.org/10.4110/in.2026.26.e4

Chokshi N, et al. Immune Netw. 2026 Oct;26(5):e38. https://doi.org/10.4110/in.2026.26.e38

The complement system is a central component of innate immunity that coordinates host defense, immune surveillance, and inflammatory responses through tightly regulated proteolytic cascades. Genetic variation within complement genes contributes substantially to interindividual differences in complement activity and disease susceptibility. While coding variants directly alter complement protein structure and function, the microRNA (miRNA)-mediated control and post-transcriptional regulation is not fully understood in shaping complement gene expression across immune and inflammatory mechanisms. Complement pathway genes exhibit extensive and heterogeneous 3′-untranslated regions (3′UTRs), which serve as primary platforms for miRNA binding and RNA-binding protein interactions. Both common and rare single-nucleotide polymorphisms within coding regions and 3′UTRs can influence miRNA targeting efficiency, disrupt regulatory motifs, or alter mRNA turnover, thereby fine-tuning complement activity rather than causing complete loss of function. Here, we systematically analyzed miRNA binding sites and single-nucleotide polymorphisms (SNPs) within the 3′UTRs of complement pathway genes spanning the classical, lectin, alternative, and terminal pathways. Our analysis uncovered heterogeneous patterns of miRNA-mediated regulation across the complement system. While core complement components showed relatively sparse conserved miRNA targeting, regulatory factors, receptors, and terminal pathway proteins emerged as densely regulated nodes, harboring multiple conserved binding sites. A broad repertoire of miRNAs was predicted to engage complement genes in a pathway-specific manner, implicating these interactions in inflammation, cancer progression, metabolic regulation, and immune signaling. SNPs within miRNA-binding regions are predicted to disrupt or create regulatory interactions, providing a mechanistic basis for how non-coding genetic variation can alter gene expression and modulate disease susceptibility. Our findings indicate miRNA-mediated post-transcriptional regulation as an important yet underappreciated layer of complement system control, providing a framework for understanding how regulatory genetic variation shapes complement-driven immune responses and disease risk.