Revisiting Bill Lands' Hypotheses: HUFA Balance, Immuno-Metabolic Regulation, and Conflicting Clinical Evidence

The optimal dietary balance between n-6 and n-3 polyunsaturated fatty acids (PUFAs), the safe upper intake of n-6 PUFAs-particularly linoleic acid-and the physiological consequences of their metabolic competition remain unresolved in the context of the Western diet. Since the 1980s, Bill Lands and colleagues have argued that high n-6 PUFA intake can shift the balance of n-3-derived pathways and eicosanoid signaling, potentially influencing processes relevant to non-communicable diseases. Across human populations, the proportion of n-6 in tissue HUFA spans a broad range-from roughly 20% in traditional dietary patterns to nearly 80% in typical Western diets-illustrating the predictable impact of dietary precursor supply on HUFA composition. Despite its potential public health implications, this hypothesis has received limited systematic attention. In this narrative review, we synthesize key aspects of Lands' work, evaluate supportive and contradictory evidence, and highlight mechanistic insights into lipid competition and inflammatory regulation. We conclude that these unresolved but testable hypotheses warrant renewed investigation, as their corroboration could reshape dietary guidelines and strategies for chronic disease prevention.